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Current Pharmaceutical Design, 2005, 11, 973-984
973
Blood-Brain Barrier Transport of Cytokines: A Mechanism for
Neuropathology
William A. Banks*
GRECC, Veterans Affairs Medical Center-St. Louis and Saint Louis University School of Medicine, Division of
Geriatrics, Department of Internal Medicine
Abstract: Cytokines circulating in the blood affect CNS function through a variety of pathways. One of these pathways is
by being transported directly across the blood-brain barrier (BBB). Transport of blood-borne cytokines across the BBB is
now known to be an operational pathway by which cytokines can directly affect CNS functions. Cytokine transport across
the BBB, however, is a complex event. Not all cytokines are transported and, for those which are, transport rates differ
among cytokines, among brain regions, with physiological circumstances, and with disease. Here we address some of the
major principles and concepts relating to cytokine transport and BBB function which have emerged as important to
neuroimmunology and neuropathology.
INTRODUCTION
As the other articles in this issue vividly illustrate,
cytokines are causally related to a host of diseases of the
central nervous system. These articles show that cytokines
induce neuropathology through a host of mechanisms which
we do understand (or are beginning to understand) and a host
which we do not. Most of the authors of this issue also now
likely suspect that neuropathology is only the tip of the
iceberg regarding the effects of CNS cytokines. As cytokines
have effects on normal behavior and events in the CNS and
as sickness behavior and many reactions to stress can be
considered adaptive (at least in their earlier stages), CNS
cytokines are probably even more important in explaining
how animals stay healthy than in explaining how they get
sick [73, 82, 83, 119, 127].
The roles that cytokines play in neuropathology are
enormously varied. Our understanding of these roles is
increasing dramatically as can be seen from the growth of
the literature in the cytokine field (Fig. 1). A search of the
National Library of Medicine shows about 4, 200 articles
that combine “cytokines” with “brain” or with “central
nervous system”. This literature has grown from only 91
publications in the five years of 1986-1990 to over 2, 200 in
1998-2002. But this is a small percentage of the total
cytokine literature of over 75, 000 articles. This larger area
has also increased dramatically, from about 3, 200 articles in
1986-1990 to over 37, 000 in 1998-2002. During this time,
the CNS has begun to receive relatively more attention. In
the 1986-1990 period, only 1 in 36 articles on cytokines was
related to the CNS; in the 1998-2002 period, the ratio was
1:17.
Cytokines can be either neuroprotective or destructive,
depending on state and concentration [99, 119]. Indeed,
nothing is particularly simple about cytokines. They do not
necessarily display classic mechanisms of control such as
negative feedback loops. Instead, cytokines display feed
back loops wherein they may either inhibit or stimulate their
own release or that of other cytokines, depending upon the
particular tissue or situation. This complexity bodes well in
the long term for the ability of cytokine mechanisms to
explain the complexities of immunology and neuroimmunology. But in the short term, it complicates investigations as
we are unable to assume many of the simplifying principles
established in other fields which investigate the effects of
substances on the CNS.
One area of investigation relates to the sources of
cytokines. The cytokines which act within the CNS can have
a number of sources of origin: neurons, astrocytes, brain
endothelial cells, microglia, and immune cells which have
entered the CNS from the periphery are some examples. The
stimulation for those sources to release their cytokines,
however, may not have originated from within the CNS. The
stimulation may have originally occurred at afferent nerves,
blood-borne cytokines acting at circumventricular organs, or
circulating immune cells. This review will concentrate on
another pathway: that of the ability of blood-borne cytokines
to cross the BBB and act directly upon brain tissue. Previous
reviews have catalogued those cytokines so far investigated
for their abilities to cross the BBB [6, 9, 114]. This review
will emphasis the principles and concepts so far established
for the transport of cytokines across the BBB.
SELECTED, RELEVANT PRINCIPLES OF THE BBB
To review the principles and concepts established for the
transport of cytokines across the BBB, we must first review
those aspects of BBB function which are relevant to the
topic. The areas of the BBB and its functions are very
complex and are growing increasingly so. Therefore, this
section cannot be exhaustive, but is meant to aid the reader
to those areas which are important for cytokine transport and
neuroimmunology.
The BBB is More Than a Barrier
*Address correspondence to this author at the WAB, 915 N. Grand Blvd, St.
Louis, MO 63106, USA; Tel: (314) 289-7084; Fax: (314) 289 6374;
E-mail: [email protected]
1381-6128/05 $50.00+.00
Originally, is was assumed that cytokines could not cross
the BBB. This assumption was made before there was any
© 2005 Bentham Science Publishers Ltd.
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William A. Banks
Fig. (1). The Growth of the Neuroimmune Literature. National Library of Medicine data base was used to determine the number of
publications relating to the terms “Cytokine” “Cytokine” combined with “CNS or Brain”, and “Cytokine” combined with “Blood-Brain
Barrier”. Over half of the neuroimmune articles have been published in the last 5 years.
real investigation of the area. In fact, when experimental
evidence was first presented raising the possibility that
cytokines could cross the BBB, it was often dismissed. Why,
in the absence of direct studies, was it reasoned that
cytokines could not cross the BBB?
The reasoning was based on the knowledge that
circulating proteins, as exemplified by albumin, are virtually
excluded from the CNS [44]. The CSF/plasma ratio for
albumin is 1:200, one of the highest gradients in biology.
Likewise, cytokines were thought to be too large and
hydrophilic to cross the BBB by the non-saturable mechanism of transmembrane diffusion. Although all of this
reasoning was logical, it failed to consider a third possibility:
that saturable carrier-mediated systems could exist for the
transport of regulatory proteins across the BBB. The BBB
was known to possess many transporters [43], but most of
these were for substances with molecular weights well below
those of cytokines. Transferrin, a substance much larger than
any cytokine, was known to be taken up by the BBB, but it
was unclear whether transferrin was actually transported
across the BBB or simply sequestered by brain endothelial
cells and subsequently re-released back into the blood.
The reasoning was no doubt reinforced by the same peril
of “constricted nomenclatures” which many peptides have
suffered. The concept of pluripotent peptides was hampered
by the custom of naming a peptide for the function which led
to its discovery [71]. For example, alpha melanocyte
stimulating hormone was named for its actions on melatonin,
which causes the skin of lower vertebrates to darken. The
assumption that one peptide would have one function made
it difficult to accept that alpha melanocyte stimulating
hormone could have profound effects on cognition [72].
Likewise, the term “blood-brain barrier” so emphasizes
barrier function, that it is difficult to remember that the BBB
is also one of the most metabolically active tissues in the
body and that practically every substance required by the
CNS must cross the BBB.
By first restricting entry and then selectively facilitating
entry, the BBB can act as a regulatory interface between the
CNS and the peripheral circulation. As such, the BBB is key
to establishing and maintaining the homeostasis of the CNS,
of supplying the nutritional needs of the CNS, and of
controlling the influx and efflux of informational molecules.
There are Multiple, Parallel BBBs
This review uses the term BBB conceptually in discussing its neuroimmune functions. This is appropriate as the
term was first used to explain why dyes could not stain CNS
tissues and why bile acids would induce seizures when
injected into the brain but not when injected into the blood
[30]. But the anatomical basis for this barrier function was
elusive until the electron microscope showed the existence of
tight junctions between the cells which comprised both the
choroid plexus and the capillary bed of the brain [129, 130,
138].
No area shows the intricacies of the BBB more than
comparing and contrasting the choroid plexus and the
vascular barrier of the brain. One the one hand, the vascular
barrier is so intimately associated with brain cells that no cell
is more than 30-40 microns from a capillary. Some have
argued that for drug delivery or widespread distribution
within the CNS, the role of the choroid plexus is minimal.
One the other hand, the choroid plexus produces 70% of the
cerebrospinal fluid [45]. In the adult mammal, there is no
anatomical barrier between the cerebrospinal fluid and brain
interstitial fluid and, to at least some degree, one fluid is
reflected in the other. Many studies evaluate CNS function
Blood-Brain Barrier Transport of Cytokines
by sampling cerebrospinal fluid; indeed, almost every study
of the BBB in humans has used cerebrospinal fluid. One
might argue that at least for practical purposes, the choroid
plexus is at least as relevant as the vascular barrier. One
caveat is that almost every study in humans has obtained its
cerebrospinal fluid from the lumbar area, not from within the
cranium. This is unfortunate, as lumbar cerebrospinal fluid
largely reflects events of the lumbar spine, not the brain [33,
62, 65]. Another caveat is that substances in the cerebrospinal fluid do not penetrate very deeply into brain tissue
[88, 90]. Brownian motion is the major force driving
molecules from the CSF into brain tissue. As a result, substances originating in cerebrospinal fluid penetrate only a few
hundred microns into brain tissue. A caveat to this, however,
is that neurons project into the ventricular lining and some
neuronal bodies are located here as well which send their
projections deep into the brain. This means that informational molecules entering the CSF are able to influence
neuronal functions in brain regions far from their diffusion
limits.
There are also barriers between the circumventricular
organs (CVOs) and the ventricles and between the CVOs
and the adjacent brain tissue [80, 81, 121, 131]. The CVOs
are small areas of the brain in which at least a portion of their
vascular beds do not form a BBB [60, 61]. This allows
circulating substances to leak into these areas much like they
do in peripheral tissues. The CVOs are adjacent to a ventricle
and also with surfaces adjoining brain regions which do have
vascular barrier function. However, barrier functions limit
the ability of the CVO contents to diffuse into the adjacent
CSF and brain tissue. The ependymal cells lining the ventricles form tight junctions between the CVO and ventricular
compartment, thus limiting CVO to CSF exchange [80, 121].
Likewise, an anatomical barrier between the CVOs and
adjacent brain tissue is well established [81, 121, 131]. This
barrier, consisting largely of tanycytes [121], develops after
birth in rodents. Autoradiographic studies have shown that a
barrier prevents interleukin-1 from diffusing out of the
CVOs into adjacent brain tissue [89, 90, 122]. However,
some other studies have provided evidence that there is some
residual leakage out of the CVO [79, 133, 135]. This may
occur at either a cerebrospinal fluid or a brain tissue
contacting area. Any leakage from CVO to brain, however,
would be limited not only by the anatomical barrier, but also
by a diffusion barrier. Diffusion within brain tissue is largely
driven by Brownian movement and so substances in brain
interstitial fluid seldom move more than a few hundred
microns from their sites of origin [38, 46, 47]. Given these
caveats, the CVOs play several critical roles in neuroimmune
function as reviewed below.
The BBB is Multifunctional
BBB transport of cytokines aside, the BBB plays many
key roles in neuroimmunology and neuropathology. On the
one hand, to the extent that the CNS is an immunoprivileged
area, it is because of the BBB’s restrictive functions. On the
other hand, to the extent that the concept of the CNS as an
immunoprivileged area needs revision, it is because of the
BBB’s selective permeability. For example, the dual roles of
the BBB in restriction and selective permeability are
important in regulating immune cell trafficking between the
Current Pharmaceutical Design, 2005, Vol. 11, No. 8 975
CNS and blood [86, 147]. Immune cells are relatively
restricted from entering the CNS, but are able to cross the
intact BBB during development, in health, and in disease.
When the functions of the BBB go awry, as in multiple
sclerosis, disease results.
Many of the BBBs (vascular, choroid plexus, CVO
interfaces) are secretory or allow non-cytokine (e.g., prostaglandins) secretions to pass. The barriers can secrete prostaglandins, nitric oxide, and neurotoxins as well as cytokines
[54, 59, 78, 132]. Whether a virus is neurovirulent depends
in part on whether it has the ability to cross the BBB [36,
139]. To do so, the virus must possess key glycoproteins, or
be able to infect immune cells which express key
glycoproteins, which interact with BBB receptors in such a
way as to route the virus (or infected immune cell) across the
BBB monolayer. Alternatively, an endotropic virus can first
infect the endothelial or epithelial cells which comprise the
BBB and subsequently be shed into the CNS.
Although it is very convenient to think of the vascular
BBB as a monolayer of endothelial cells, it is equally valid
to think of the BBB as also containing other cells, such as
astrocytes and pericytes and being surrounded by a
glycocalyx. This view is especially useful for neuroimmunology. Pericytes, microglia, and astrocytes have active
immune roles and are involved in cross talk with brain
endothelial cells [54, 140, 142]. Pericytes and astrocytes do
not physically form another layer of barrier to most
substances, but the glycocalyx can form a barrier to viralsized structures [102].
The CVOs and Neuroimmunology
The lack of a vascular BBB within CVOs allows
circulating materials to enter these regions of the CNS and
act directly on their cellular elements. The CVO both sends
and receives neuronal projections to and from various areas
of the brain [56, 68]. This means that the influence of the
CVOs is exerted in areas far from their borders. Recently, it
has been proposed that one CVO (the area postrema) forms
with the dorsal vagal complex an especially important
junction for neuroimmune signaling to the brain [91]. This
area brings together a CVO and the vagal afferents, two
important pathways in neuroimmune communication. It has
been pointed out that this location also contains brain areas
with normal BBB function and a region in contact with the
CSF [7]. As a result, all the major pathways proposed for
neuroimmune communication converge in this one location
(Fig. 2).
Diffusion of interleukin-1 out of CVOs into the adjacent
brain tissue does not occur to any great extent [89, 122].
Some studies indicate that there is a leakage of serum
proteins at the border between the CVO and adjacent brain
neuropile [79, 133, 135], whereas other studies dispute this
[80, 81, 121, 131]. Autoradiographic studies have shown that
the two outer-most cell layers comprising the CVO act as a
barrier [89]. This is consistent with a delimiting membrane
surrounding the CVOs [80, 81, 131] which recently has been
shown to be comprised of tanycytes [121]. This tanycytic
barrier develops after birth in rodents, at least for the median
eminence. This may mean that blood-to-brain communication may be different in neonates and adults.
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William A. Banks
Fig. (2). Neuroimmune Communication Pathways. The Vagus and three compartments [Circumventricular Organs (CVO);
Ventricular/Cerebrospinal Fluid (CSF); Brain] are illustrated. Key to Structures: Brown represents blood vessels (leaky in CVO and CSF
compartments; not leaky (forming blood-brain barrier) in Brain compartment). Pink: ependymal lining forming the choroid plexus. Yellow:
tanycytic and ependymal cell linings forming barriers between CVO/CSF and CVO/Brain compartments, but leaky between CSF/Brain
compartments. Blue-green: neurons and other cells of the CNS. Tan with blue centers represents immune cells in or derived from the
circulation. Blue: vagus nerve. Large red arrows represent immune cells derived from the circulation entering the CVO or Brain
compartments. Small red arrows represent neuroimmune substances derived from circulation or from immune cells. Green lines represent
secretions from barrier cells (tanycytic, ependymal, and endothelial). Black lines represent projections from vagus nerve. Box with broken
lines represents the neurovascular unit. Key to Pathways: Neuroimmune substances in or derived from the circulation or from immune cells
derived from the circulation (5) can interact with cells in adjacent tissue (1), including barrier cells (2), or cross the blood-brain and tanycyte
barriers (3). Barrier cells can also be a source of neuroimmune substances (4). The vagus projects (6) to barrier cells, blood vessels, and
neurons and into the CVOs. The CVOs project neural elements into the Brain compartment (7) and receive neural input from the brain (8)
and from the vagus (6). For simplicity, CSF/choroid plexus pathways are not illustrated. Reproduced with permission from [7].
The evidence strongly suggests that CVOs do release a
number of substances into their immediate vicinity, such as
prostaglandins [78]. Whether these substances include
cytokines, perhaps released from or transported across the
tanycytic barrier, is unclear. Substances released in this
manner would be limited in how far they could diffuse. But
these substances could affect distant brain regions by
interacting with neurons projecting to or from other brain
regions [56, 68]. A substance originating from a CVOs could
also stimulate adjacent cells to release substances which, in
turn, would induce other adjacent cells to release substances
thus propagating the signal through brain tissue.
PERMEABILITY OF THE BBB TO CYTOKINES
Many Cytokines Cross the BBB
Several cytokines have been studied for their ability to
cross the BBB (Table 1). In choosing a cytokine for study,
one would concentrate on cytokines whose actions might be
explained based on their ability to cross the BBB. Therefore,
given that some cytokines can cross the BBB, it is not
surprising that the majority of cytokines so far studied have
been found to be transported across the BBB by saturable
transport systems (Table 1).
Blood-Brain Barrier Transport of Cytokines
Table 1.
Current Pharmaceutical Design, 2005, Vol. 11, No. 8 977
Cytokine Interactions With the Blood-Brain Barrier. Cytokines are Categorized with Regard to their Predominant
Interaction with the BBB: Blood-to-Brain Saturable Transport; Brain-to-Blood Saturable Transport, Blood-to-Brain
Non-Saturable Passage; Luminal Association. In rare Instances Where Two Interactions Occur, a Cytokine is Listed
More Than Once. Unless Otherwise Specified, Cytokines are Tested in Mouse
Blood-to-Brain Saturable Transport
human or murine IL-1 alpha
murine IL-1 beta
rat IL-1 alpha in rat
human IL-1 Receptor Antagonist
murine TNF
rat TNF in rat
human IL-6 in mouse or rat
murine IL-6
human NGF in mouse or rat
human NT3 in mouse or rat
human BDNF in mouse and rat
Fibroblast Growth Factors in rat and gerbil
human Epidermal Growth Factor
human Leukemia Inhibitory Factor
Ciliary Neurotrophic Factor
murine Interferon gamma
murine Granulocyte Macrophage-colony Stimulating Factor
Reference
[18, 26]
[26]
[123]
[64]
[63]
[103]
[20, 85]
[20]
[107, 124]
[107, 124]
[104, 124]
[40, 41, 144]
[110]
[115]
[116, 124]
[106]
[93]
Brain-to-Blood Saturable Transport
murine IL-2
[25]
Blood-to-Brain Non-Saturable Passage
rat Cytokine-induced Neutrophil Chemoattractant-1
[111]
Luminal Association
Macrophage Inflammatory Proteins (1 alpha and 1 beta)
human Transforming Growth Factor
human Leukemia Inhibitory Factor
[16]
[118]
[115]
Little or No Blood-to-Brain Passage
human IL-1 alpha in rat
human IL-1 beta
human TNF
human TNF in rat
human or murine IL-2
Macrophage Inflammatory Proteins (1 alpha and 1 beta)
human Transforming Growth Factor
murine Interferon alpha
IL-10
GDNF
[123]
[8]
[19]
[103]
[25, 145]
[16]
[118]
[106]
[70]
[69]
Abbreviations: IL: interleukin; TNF: tumor necrosis factor alpha, NGF: nerve growth factor; NT3: neurotrophin-3; BDNF: brain-derived neurotrophic factor; GDNF: glial cell linederived neurotrophic factor.
The first cytokines to be studied were the interleukin-1's
[18, 26]. Interleukin-1 alpha is particularly easy to study
because it is easily labeled with radioactive iodine and
retains its biological activity after being labeled [50].
Interleukin-1 beta is more difficult to label and only retains
80% of its biological activity. Both of these interleukins
share with interleukin-1 receptor antagonist a transporter or
family of transporters [18, 64]. As such, most conclusions
about transport of interleukin-1 alpha can be extrapolated, at
least tentatively, to interleukin-1 beta and interleukin-1
receptor antagonist.
Two other proinflammatory cytokines, tumor necrosis
factor-alpha (TNF) and interleukin-6, were the next two
cytokines to be studied [20, 63]. Their saturable transport has
been confirmed [85, 103]. Since then, over a dozen cytokines
have been assessed for their blood-to brain transport (Table
1). Several of these are transported across the BBB.
Cytokine-induced neutrophil chemoattractant-1 crosses the
BBB to a measurable degree by a non-saturable mechanism
[77]. Other cytokines cannot be shown to cross the BBB to
any degree whatsoever (Table 1).
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Current Pharmaceutical Design, 2005, Vol. 11, No. 8
One of the cytokines which is not transported from
blood-to-brain is interleukin-2 (IL-2). Interestingly, several
mechanisms work together to prevent IL-2 from crossing the
BBB. Not only is there not a blood-to-brain transporter for
IL-2 [25], but IL-2 is transported by a saturable mechanism
out of the CNS, possibly by the P-glycoprotein transporter
[51]. IL-2 is also rapidly degraded either in brain or at the
BBB. Blood-to-brain passage of IL-2 is further retarded by a
circulating substance, possibly a soluble receptor for IL-2
[25]. As a rule, therefore, acutely administered radioactive
IL-2 cannot be demonstrated to cross the BBB.
However, early studies showed that when given in
therapeutic doses in disease states, some IL-2 entered the
CSF [136]. It may be that this IL-2 entered the CNS by way
of the residual leakiness of the BBB in the way that albumin
does, that the BBB was compromised in these patients, that
the human BBB handles IL-2 in a way different from that of
rodents, or that multiple injections of IL-2 induces a
transporter at the BBB for it.
Brain-to-Blood Transport of Cytokines
Glucose and amino acids are transported across the BBB
by the saturable, non-energy requiring mechanism of
facilitated diffusion. Because these substances have levels
which are higher in serum than in brain interstitial fluid, they
are transported in the blood-to-brain direction. But facilitated
diffusion is a bidirectional process, with net movement being
from the side with the higher to the side with the lower
concentration. This bidirectional transport is easy to demonstrate with the use of radioactively labeled ligands or by
altering the brain or blood concentrations of the ligand [42,
125]. Cytokines, as a rule, do not have a saturable bidirectional transport system. For example, saturable transport for
the interleukin-1s, TNF, and IL-6 are only in the blood-tobrain direction [20, 26, 63].
Only one cytokine to date has been found to have a
saturable component in its brain-to-blood efflux [25].
Neither of these cytokines are transported by a saturable
mechanism into the brain. As discussed above, the unidirectional efflux system for IL-2 is one of the reasons IL-2 does
not readily cross the BBB. Although most cytokines are not
transported out of the CNS by a saturable mechanism, they
nonetheless do move in the brain-to-blood direction by the
mechanism of bulk flow [20, 26, 34, 35, 63]. Bulk flow is
the term used to describe the absorption of CSF into the
blood. Any substance found in the CSF will be absorbed into
blood by this mechanism. Because cytokines are not rapidly
cleared from blood, bulk flow can result in high levels of
cytokine in blood [34, 35]. For example, a cytokine injected
into the lateral ventricle of the brain can eventually attain
higher blood levels than if the cytokine were injected
intravenously. This suggests that the CNS can be a source of
cytokines in blood.
CSF is cleared from the CNS by two pathways: direct
absorption into blood at the arachnoid villi; clearance by the
brain’s primitive lymphatics [28, 31, 53, 74, 146]. This latter
route means that CSF cytokines can travel directly from the
CNS to the cervical lymphatics. This route has been shown
to be able to regulate immune responses [39, 76].
William A. Banks
Transport Systems are Specific
The cytokine transport systems are specific for closely
related cytokines. For example, cross inhibition studies have
shown that a transporter or family of transporters is responsible for the blood-to-brain influx of the IL-1s [26, 64].
However, the IL-1 system does not transport TNF or IL-6
[20, 63]. Each of these cytokines has its own distinct system.
These systems are specific in another sense as well. The IL-1
transporter, as studied in the mouse, will transport both
murine and human IL-1 alpha [26]. It will also transport
murine IL-1 beta, but not human IL-1 beta [8]. However, the
murine transporter favors murine over human IL-1 alpha and
favors murine IL-1 alpha over murine IL-1 beta [26]. In the
rat, the IL-1 transporter will transport rat, but not human, IL1 alpha [123]. Similarly, human TNF is not transported in all
mouse strains or in the rat [19, 103].
The rate of transport also varies among the transporters
and cytokines. Most of the saturable systems transport a
cytokine at a rate of about 10-4 ml/g-min with about 0.1% of
the iv injected dose taken up per g of brain (%Inj/g).
However, IL-1 receptor antagonist is taken up at a rate of
closer to 10-3 ml/g-min, with about 0.3-0.6 %Inj/g [64]. The
nerve growth factor (NGF) family of cytokines also
demonstrates a range of uptakes. [84, 107, 124]
The most impressive uptake of a cytokine, however, is
that of BDNF [104]. Its transport across the BBB has been
demonstrated independently by two laboratories [104, 124].
Its rate of entry into brain is about 0.2 ml/g-min when
assessed with the brain perfusion method. This rate is similar
to that for some amino acids.
Other Cytokine-BBB Interactions
Cytokines can disrupt the BBB [48, 94, 128, 134]. This
was one of the first observations of a cytokine-BBB
interaction. As a result, it is often assumed that any elevation
in cytokines is accompanied by a deterioration of the BBB or
even that disruption is the main mechanism by which
cytokines affect BBB function. However, it is actually quite
difficult to disrupt the BBB with cytokines, at least with
acute administration [13, 26]. For example, high, repeated
doses of lipopolysaccharide (LPS) are needed to disrupt the
BBB [98, 148]. In contrast, LPS can affect other aspects of
BBB permeability in the absence of BBB disruption. The
activity of the saturable transporter for insulin is greatly
upregulated by LPS under paradigms that do not necessarily
affect BBB integrity [148]. Absorptive endocytosis of
gp120, the viral coat of HIV-1, is also enhanced by LPS
[98]. Disruption of the BBB to serum proteins is most likely
a pathological event, including when disrupted by cytokines,
and is more likely akin to a terminal event than a normal
physiological reaction.
The BBB and cytokines interact in several important
ways other than just transport. Some cytokines associate
with the BBB without being transported across the BBB. For
example, blood-borne macrophage inflammatory proteins
stick to a high degree to the luminal surface of the vascular
BBB [16]. This is consistent with a binding site for the MIPs
on brain endothelial cells [3]. Transforming growth factor
Blood-Brain Barrier Transport of Cytokines
also binds to brain endothelial cells without being transported across the BBB [118].
The BBB itself can release cytokines [54, 59, 132]. HIV1 and its viral coat protein, gp120, induce the release of
endothelin-1, a cytokine, from monolayer cell co-cultures of
brain endothelial cells and astrocytes [49]. Studies have also
shown that brain endothelial cells can take up cytokines from
their abluminal (brain side) surface and translocate them to
the luminal surface. Here, they could interact with
circulating immune cells [95].
In contrast to the cytokines, the soluble receptors for
cytokines do not cross the BBB [27]. In fact, binding to a
circulating soluble receptor inhibits a cytokine from crossing
the BBB. Retardation of cytokine transport across the BBB
is, therefore, another possible mechanism by which circulating soluble receptors can influence neuroimmune actions. A
circulating substance, postulated to be a soluble receptor,
binds IL-2 to retard its passage across the BBB [25].
Radioactively labeled BDNF also circulates in a large
molecular weight form, indicating it is likely associated with
a soluble receptor, binding protein, or circulates in aggregated from [104]. Of these possibilities, it is more likely that
BDNF is associated with a soluble receptor or binding
protein in the blood. Such an association could explain the
1000 fold increase in transport across the BBB when assessed with the brain perfusion method [104], a method which
negates the influence of circulating proteins [141, 143].
Enough Cytokine Crosses the BBB to Affect CNS
Function
A critical question is whether enough cytokine crosses
the BBB to have effects on the CNS. Three levels of
argument have been advanced to support that BBB transport
rates of cytokines are sufficient to produce CNS effects.
The first argument is teleological: given that a transporter
for a cytokine exits, it must be doing something. Production
and maintenance of transporters is metabolically expensive
and it would be unlikely that the BBB would have specific
transporters for which there was no function.
The second level of argument is that the amounts of
cytokine transported into brain are substantial. The amounts
of cytokine transported can be comparatively assessed in
three ways: the rate of passage; the amount of an
intravenously injected dose that enters the brain; the steady
state brain/blood ratio. For cytokines entering the brain by
saturable transporters, a typical rate of entry is in the 10-3 to
10-4 ml/g-min. This rate is about 40-100 times faster than
that of albumin, a substance largely restricted from the CNS,
and about 100-1000 times slower than the entry of glucose
and amino acids into the brain. Leptin, a 16 kDa substance
which is secreted by fat and is transported across the BBB to
exert its effects within the CNS at a cytokine-like receptor,
has a transport rate of about of about 4(10-4) ml/g-min.
Morphine and domoic acid also crosses the BBB at about
this rate [1, 15, 126]. The percent of intravenously injected
cytokine which enters the brain ranges from about 0.050.3%. This compares favorably to the values for other substances known to exert effects on the CNS, such as morphine
(0.018 %inj/g) [15], pituitary adenylate cylcase activating
Current Pharmaceutical Design, 2005, Vol. 11, No. 8 979
polypeptide (0.11 %inj/g) [22], leptin (0.17 %inj/g) [21],
acetaminophen (0.11 %inj/g) [37], synthetic opiate peptides
such as biphalin (0.051 %inj/g) [66], and domoic acid (0.002
%inj/g) [126]. Steady state is the most difficult to compare to
other substances, but a brain/serum ratio of 0.12 of
chronically infused interleukin-1 [17] compares favorably to
the cerebrospinal fluid /serum ratios of 0.01-0.05 for many
peptides and regulatory proteins and the brain/serum ratio of
0.052 for endogenous insulin [10]. These arguments, in
general, show that the amounts of cytokine entering the brain
are comparable to amounts entering the brain of substances
known to have direct effects on the CNS.
The third level of argument is based on direct
experimental results. It has been shown that the impairment
in memory in mice induced by intravenously injected human
interleukin-1 can be prevented by injecting a blocking
antibody specific for human interleukin-1 into the posterior
division of the septum [8]. These results could only be
achieved if the cytokine mediating cognitive impairment was
acting within the posterior division of the septum and was
derived from blood-borne interleukin-1. Similarly, bloodborne fibroblast growth factor is transported across the BBB
to regulate neurogenesis in the olfactory bulb [144]. The
transport of fibroblast growth factor into brain also likely
underlies a neuroprotective role after ischemia [40].
The above studies carefully showed that the cytokine
appearing in the brain was derived from cytokine which was
originally in the blood. A cytokine in the circulation,
however, can also elevate its levels in the CNS by inducing
release from brain endothelial cells, glia, neurons, or other
cells within the CNS, including immune cells. Usually it is
difficult to determine the degree to which cytokines in brain
originated from a central or peripheral source.
Cytokine Transporters do Not have to be Induced
Some cytokines, such as the IL-1's, are not normally
circulating in blood, whereas others are. The cytokine
transporters, including that for the IL-1's, are constitutively
expressed in the mouse and rat. That is, they are available for
cytokine when it occurs in the circulation.
Why a transporter should be readily available for a
substance that is not constantly circulating is unclear. It may
be that the time required to induce cytokine transporter
production would delay brain signaling too long for the
transporter to be effective. In this sense, having transporters
readily available is similar to having an adequate number of
receptors readily available to react to cytokine appearance;
that is, transporters and receptors are part of the infrastructure which needs to be maintained for the organism to
rapidly respond to infection. It may also be that the
transporters are in constant use. It need not be that IL-1
levels are present but below assay detection limits. It may be
that immune cells adhering to brain endothelia release their
contents into a microenvironment as appears to occur in the
case of defensins [137].
Interestingly, the BBB also constitutively expresses the
P-glycoprotein transporter, a brain-to-blood efflux system.
The P-glycoprotein transporter is present in immune cells as
well, but usually only present when induced. One of the
980
Current Pharmaceutical Design, 2005, Vol. 11, No. 8
ligands for P-glycoprotein in immune cells is IL-2 [51].
Whether P-glycoprotein is also the transporter for IL-2 at the
BBB remains to be tested.
Regional Variation of Cytokine Transport
Cytokine transporters are not uniformly active
throughout the CNS. Nor does a given region of the brain
equally transport all cytokines (Fig. 3). The most outstanding
example to date is the highly selective uptake of IL-1 alpha
by the posterior division of the septum [87]. Transport of
blood-borne IL-1 alpha across the BBB of the posterior
division of the septum is important in mediating the effects
William A. Banks
of IL-1 alpha on memory [8]. Other brain regions do not take
up IL-1 alpha at all [97]. For the remaining brain regions, IL1 alpha uptake varies little (Fig. 3, upper panel). In
comparison, TNF is taken up by all brain regions, but uptake
varies among regions by 10 fold [23]. Nerve growth factors
also show a great deal of regional variation in uptake [124].
As recently reviewed, differences between brain and spinal
cord (Fig. 3, lowerpanel) can be negligible for some
cytokines but dramatic for others [114].
This diversity of transport may underlie a mechanism of
regulation. Regional variation in cytokine transport means
that not all regions of the brain will receive the same
Fig. (3). Transport Rates Across the BBB Varies Among Cytokines and Brain Regions. Upper Panel: IL-1 alpha and TNF transport shows
differences from each other and among regions. Data from [23, 97]. Lower Panel: Some cytokines have different rates of transport into brain
and spinal cord. Data from [93, 106, 115, 120].
Blood-Brain Barrier Transport of Cytokines
peripheral input. Variation among cytokines for a given
brain region means that the influence of some cytokines will
be greater than others.
Cytokine Transporters vs Cytokine Receptors
To date, no transporter for a cytokine has been isolated.
The untested assumption in some articles has been that a
short form of the cytokine receptor is commandeered by the
endothelial cell for use as a transporter. This assumption has
been tested for IL-1, TNF, and epidermal growth factor [5,
26, 110, 113]. In vitro and in vivo studies show that the
binding site for IL-1 is different between the IL-1 transporter
and the IL-1 type 1 receptor. Likewise, studies with knockout mice show that the receptor and transporter for epidermal
growth factor are different gene products. For TNF, however, both the p55 or p75 receptors can act as transporters.
Cytokine Transporters are Regulated and Affected by
Neuropathology
Brain region and cytokine (e.g., IL-1 vs TNF) are not the
only variants for rate of transport. BBB transporters for
peptides and regulatory proteins are not static, but affected
by physiology and disease. The first such example for a
cytokine was the finding that aluminum inhibited IL-1
transport across the BBB [18]. Aluminum is a neurotoxin in
humans [2, 29] and animals [29, 32, 52] and alters the BBB
permeability to many substances [4, 11, 12, 67, 75].
Proposed mechanisms for the effects of aluminum on BBB
function include displacement of an ionic cofactor, alteration
of Debye length, or alterations of an aspect of membrane
fluidity [14].
Transport rates of radioactive cytokines also show a
diurnal rhythm [19, 109]. Part of this transporter variation
may be reflecting alterations in blood levels of cytokines
[149].
Transport of TNF is enhanced in experimental allergic
encephalomyelitis, an animal model of multiple sclerosis
[108]. This enhancement is to the saturable component of
TNF transport and is not dependent on BBB disruption. The
rate of TNF transport returns to normal with the resolution of
the clinical signs of EAE. TNF transport is also altered with
spinal cord and brain injury [105, 112, 117, 120]. Injury in
one portion of the CNS can alter transport characteristics in
another part of the CNS and alterations in transport may vary
with the characteristics of the injury.
LPS has several effects on BBB function. It enhances the
passage of gp120, the viral coat protein of HIV-1, across the
BBB by the mechanism of adsorptive endocytosis [98]. It
disrupts the BBB by a prostaglandin-dependent, nitric oxideindependent mechanism and enhances the saturable transport
of insulin across the BBB by a prostaglandin-independent,
nitric-oxide dependent mechanism [148]. Although LPS
likely produces these effects through release of cytokines, it
is unclear which cytokines are involved. Interestingly,
neither LPS nor cardiac arrest alters the saturable transport of
TNF [96, 103].
Cytokine transport varies among strains of mice,
suggesting a genetic component to transporter regulation.
For example, fewer regions of the brain transport IL-1 alpha
Current Pharmaceutical Design, 2005, Vol. 11, No. 8 981
in SAMP8 mice than in CD-1 mice [97], but there are no
strain differences for TNF [23]. The SAMP8 mouse has a
natural mutation so that as it ages, it overexpresses amyloid
precursor peptide, has increased brain levels of amyloid beta
protein and decreased levels of acetycholine, and develops
deficits in learning and memory [24, 55, 57, 58, 100, 101].
As such, it is used as a mouse model of Alzheimer’s disease.
Therefore, strain differences suggest that overexpression of
amyloid precursor peptide may alter some BBB transporters.
Interleukin-1 beta transport has also been noted to be reduced
with aging, possibly explaining age-related decreases in
fever [92].
SUMMARY
Many cytokines are transported across the BBB by
saturable systems. This transport has been shown to be one
mechanism by which blood-borne cytokines can exert their
effects on brain. These transporters are highly selective for
their ligands. The transporters are not homogeneously distributed throughout the CNS nor are all cytokines transported
similarly for a given brain region. Transporters are also
affected by numerous physiological and pathological conditions. Together, these complexities of BBB-cytokine interactions suggest that this mechanism likely underlies many
neuropathological events.
REFERENCES
References 150-152 are related articles recently published in
Current Pharmaceutical Design.
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
Advokat C, Gulati A. Spinal transection reduces both spinal
antinociception and CNS concentration of systemically
administered morphine in rats. Brain Res 1991; 555: 251-258.
Alfrey AC, Mishell JM, Burks J. Syndrome of dyspraxia and
multifocal seizures associated with chronic hemodialysis. Trans
Am Soc Artif Inter Organs 1972; 18: 257-261.
Andjelkovic AV, Pachter JS. Characterization of binding sites for
chemokines MCP-1 and MIP-1 alpha on human microvessels. J
Neurochem 2000; 75: 1898-1906.
Audus KL, Holthaus SR, Van Bree JBMM, Shinogle JA.
Aluminum effects on growth of brain microvessel endothelial cells
in primary culture. Res Comm Chem Path Pharmacol 1988; 60: 7185.
Banks WA. Characterization of IL 1α binding to mouse brain
endothelial cells. J Pharmacol Exp Ther 1999; 291: 665-670.
Banks WA. Cytokines, CVOs, and the blood-brain barrier. In:
Psychoneuroimmunology (3rd edition), Chapter 18. Robert Ader,
David Felton, Nicholas Cohen (Eds.) Academic Press, 2001; p.
483-497.
Banks WA. Neuroimmune networks and communication pathways:
the importance of location. Brain, Behavior, and Immunity 2004;
18: 120-122.
Banks WA, Farr SA, La Scola ME, Morley JE. Intravenous human
interleukin-1α impairs memory processing in mice: Dependence on
blood-brain barrier transport into posterior division of the septum. J
Pharmacol Exp Ther 2001; 299: 536-541.
Banks WA, Farr SA, Morley JE. Entry of blood-borne cytokines
into the central nervous system: Effects on Cognitive Processes.
NeuroImmunoModulation 2003; 10: 319-327.
Banks WA, Jaspan JB, Kastin AJ. Selective, physiological
transport of insulin across the blood-brain barrier: Novel
demonstration by species-specific enzyme immunoassays. Peptides
1997; 18: 1257-1262.
Banks WA, Kastin AJ. Aluminium increases permeability of the
blood-brain barrier to labelled DSIP and β-endorphin: possible
implications for senile and dialysis dementia. Lancet 1983; ii:
1227-1229.
982
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
Current Pharmaceutical Design, 2005, Vol. 11, No. 8
Banks WA, Kastin AJ. Aluminum alters the permeability of the
blood-brain barrier to some non-peptides. Neuropharmacology
1985; 24: 407-412.
Banks WA, Kastin AJ. The interleukins -1α, -1β, and -2 do not
disrupt the murine blood-brain barrier. Int J Immunopharmac 1992;
14: 629-636.
Banks WA, Kastin AJ. Effects of aluminum on blood-brain barrier
structure and function. Life Chem Reports 1994; 11: 141-149.
Banks WA, Kastin AJ. Opposite direction of transport across the
blood-brain barrier for Tyr-MIF-1 and MIF-1: comparison with
morphine. Peptides 1994; 15: 23-29.
Banks WA, Kastin AJ. Reversible association of the cytokines
MIP-1α and MIP-1β with the endothelia of the blood-brain barrier.
Neurosci Lett 1996; 205: 202-206.
Banks WA, Kastin AJ. Relative contributions of peripheral and
central sources to levels of IL-1α in the cerebral cortex of mice:
assessment with species-specific enzyme immunoassays. J
Neuroimmunol 1997; 79: 22-28.
Banks WA, Kastin AJ, Durham DA. Bidirectional transport of
interleukin-1 alpha across the blood- brain barrier. Brain Res Bull
1989; 23: 433-437.
Banks WA, Kastin AJ, Ehrensing CA. Diurnal uptake of circulating
interleukin-1α by brain, spinal cord, testis and muscle.
NeuroImmunoModulation 1998; 5: 36-41.
Banks WA, Kastin AJ, Gutierrez EG. Penetration of interleukin-6
across the blood-brain barrier. Neurosci Lett 1994; 179: 53-56.
Banks WA, Kastin AJ, Huang W, Jaspan JB, Maness LM. Leptin
enters the brain by a saturable system independent of insulin.
Peptides 1996; 17: 305-311.
Banks WA, Kastin AJ, Komaki G, Arimura A. Passage of pituitary
adenylate cyclase activating polypeptide1-27 and pituitary adenylate
cyclase activating polypeptide1-38 across the blood-brain barrier. J
Pharmacol Exp Ther 1993; 267: 690-696.
Banks WA, Moinuddin A, Morley JE. Regional transport of TNF-α
across the blood-brain barrier in young ICR and young and aged
SAMP8 mice. Neurobiol Aging 2001; 22: 671-676.
Banks WA, Morley JE. Memories are made of this: recent
advances in understanding cognitive impairments and dementia. J
Gerontology 2003; 58A: M314-21.
Banks WA, Niehoff ML, Zalcman S. Permeability of the mouse
blood-brain barrier to murine interleukin-2: Predominance of a
saturable efflux system. Brain, Behavior, and Immunity 2004; 18:
434-42.
Banks WA, Ortiz L, Plotkin SR, Kastin AJ. Human interleukin (IL)
1α, murine IL-1α and murine IL-1β are transported from blood to
brain in the mouse by a shared saturable mechanism. J Pharmacol
Exp Ther 1991; 259: 988-996.
Banks WA, Plotkin SR, Kastin AJ. Permeability of the blood-brain
barrier to soluble cytokine receptors. Neuro Immuno Modulation
1995; 2: 161-165.
Boulton M, Flessner M, Armstrong D, Mohamed R, Hay J,
Johnston M. Contribution of extracranial lymphatics and arachnoid
villi to the clearance of a CSF tracer in the rat. Am J Physiology
1999; 276: R818-R823.
Bowdler NC, Beasley DS, Fritze EC, Goulette AM, Hatton JD,
Hession J, et al. Behavioral effects of aluminum ingestion on
animal and human subjects. Pharmacol Biochem Behav 1979; 10:
505-512.
Bradbury M. The Concept of a Blood-Brain Barrier. John Wiley
and Sons, Chichester 1979.
Bradbury MW, Cole DF. The role of the lymphatic system in
drainage of cerebrospinal fluid and aqueous humour. J Physiol
(London) 1980; 299: 353-365.
Bugiani O, Ghetti B. Progressing encephalomyelopathy with
muscular atrophy, induced by aluminum powder. Neurobiol Aging
1982; 3: 209-222.
Bulat M, Zivkovic B. Neurochemical study of the cerebrospinal
fluid. 1978; 57-89.
Chen G, Castro WL, Chow HH, Reichlin S. Clearance of 125Ilabelled interleukin-6 from brain into blood following
intracerebroventricular injection in rats. Endocrinology 1997; 138:
4830-4836.
Chen G, Reichlin S. Clearance of [125I]-tumor necrosis factor-α
from the brain into the blood after intracerebroventricular injection
into rats. Neuroimmunomodulation 1998; 5: 261-269.
William A. Banks
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
Chou S, Dix RD. Viral infections and the blood-brain barrier. 1989;
449-468.
Courade JP, Besse D, Delchambre C, Hanoun N, Hamon M,
Eschalier A, et al. Acetaminophen distribution in the rat central
nervous system. Life Sci 2001; 69: 1455-1464.
Cserr HF, Berman BJ. Iodide and thiocyanate efflux from brain
following injection into rat caudate nucleus. Am J Physiol 1978; 4:
F331-F337.
Cserr HF, Knopf PM. Cervical lymphatics, the blood-brain barrier
and the immunoreactivity of the brain: a new view. Immunol
Today 1992; 13: 507-512.
Cuevas P, Carceller F, Munoz-Willery I, Gimenez-Gallego G.
Intravenous fibroblast growth factor penetrates the blood-brain
barrier and protects hippocampal neurons against ischemiareperfusion injury. Surg Neurol 1998; 49: 77-83.
Cuevas P, Fermamdez-Ayerdi A, Carceller F, Colin S, Mascarelli
F, Munoz-Willery I, et al. Central nervous system distribution of
fibroblast growth factor injected into the blood stream.
Neurological Research 1996; 18: 267-272.
Davson H, Hollingsworth JG, Carey MB, Fenstermacher JD.
Ventriculo-cisternal perfusion of twelve amino acids in the rabbit. J
Neurobiol 1982; 13: 293-318.
Davson H, Segal MB. Special aspects of the blood-brain barrier.
Physiology of the CSF and Blood-Brain Barriers. Boca Raton,
CRC Press 1996; 303-485.
Davson H, Segal MB. The proteins and other macromolecules of
the CSF. Physiology of the CSF and the blood-brain barrier. Boca
Raton, CRC Press 1996; 573-606.
Davson H, Segal MB. The secretion of the cerebrospinal fluid.
Physiology of the CSF and Blood-Brain Barriers. Boca Raton,
CRC Press 1996; 193-255.
de Lange EC, Bouw MR, Mandema JW, Danhof M, De Boer AG,
Breimer DD. Application of intracerebral microdialysis to study
regional distribution kinetics of drug in rat brain. Br J Pharmacol
1995; 116: 2538-2544.
de Lange ECM, Bouw MR, Danhof M, De Boer AG, Breimer DD.
Application of intracerebral microdialysis to study regional
distribution kinetics of atenolol and acetaminophen in rat brain.
1993; 93-106.
Deli MA, Descamps L, Dehouck MP, Cecchelli R, Joo F, Abraham
CS, et al. Exposure of tumor necrosis factor-α to luminal
membrane of bovine brain capillary endothelial cells cocultured
with astrocytes induces a delayed increase of permeability and
cytoplasmic stress fiber formation of actin. J Neurosci Res 1995;
41: 717-726.
Didier N, Banks WA, Creminon C, Dereuddre-Bosquet N,
Mabondzo A. Endothelin-1 production at the in-vitro blood-brain
barrier during HIV infection. Neuroreport 2002; 13: 1179-83.
Dower SK, Kronheim SR, Hopp TP, Cantrel M, Deely M, Gillis S,
et al. The cell surface receptors for interleukin-1α and interleukin1β are identical. Nature 1986; 324: 266-268.
Drach J, Gsur A, Hamilton G, Zhao S, Angerler J, Fiegl M, et al.
Involvement of P-glycoprotein in the transmembrane transport of
interleukin-2 (IL-2), IL-4, and interferon-gamma in normal human
T lymphocytes. Blood 1996; 88: 1747-1754.
Ebina Y, Okada S, Hamazaki S, Midorikawa O. Liver, kidney, and
central nervous system toxicity of aluminum given
intraperitoneally to rats: a multiple-dose subchronic study using
aluminum nitrilotriacetate. Toxicol Appl Pharmacol 1984; 75: 211218.
Esiri MM, Gay D. Immunological and neuropathological
significance of the Virchow-Robin space. J Neurol Sci 1990; 100:
3-8.
Fabry Z, Fitzsimmons KM, Herlein JA, Moninger TO, Dobbs MB,
Hart MN. Production of the cytokines interleukin 1 and 6 by
murine brain microvessel endothelium and smooth muscle
pericytes. J Neuroimmunol 1993; 47: 23-34.
Farr SA, Banks WA, Uezu K, Sano A, Gaskin FS, Morley JE.
Antibody to beta-amyloid protein increases acetylcholine in the
hippocampus of 12 month SAMP8 male mice. Life Sci 2003; 73:
555-562.
Ferguson AV. The area postrema: a cardiovascular control centre at
the blood-brain interface? Canadian Journal of Physiology &
Pharmacology 1991; 69: 1026-1034.
Blood-Brain Barrier Transport of Cytokines
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
[79]
[80]
Flood JF, Harris FJ, Morley JE. Age-related changes in
hippocampal drug facilitation of memory processing in SAMP8
mice. Neurobiol Aging 1996; 17: 15-24.
Flood JF, Morley JE. Learning and memory in the SAMP8 mouse.
Neurosci Biobehav Rev 1998; 22: 1-20.
Frigerio S, Gelati M, Ciusani E, Corsini E, Dufour A, Massa G, et
al. Immunocompetence of human microvascular brain endothelial
cells: cytokine regulation of IL-1beta, MCP-1, IL-10, sICAM-1 and
sVCAM-1. J Neurol 1998; 245: 727-730.
Gross PM, Blasberg RG, Fenstermacher JD, Patlak CS. The
microcirculation of rat circumventricular organs and the pituitary
gland. Brain Res Bull 1987; 18: 73-85.
Gross PM, Weindl A. Peering through the windows of the brain. J
Cereb Blood Flow Metab 1987; 7: 663-672.
Grundy HF. Circulation of cerebrospinal fluid in the spinal region
of the cat. J Physiol (London) 1962; 163: 457-465.
Gutierrez EG, Banks WA, Kastin AJ. Murine tumor necrosis factor
alpha is transported from blood to brain in the mouse. J
Neuroimmunol 1993; 47: 169-176.
Gutierrez EG, Banks WA, Kastin AJ. Blood-borne interleukin-1
receptor antagonist crosses the blood-brain barrier. J
Neuroimmunol 1994; 55: 153-160.
Hammerstad JP, Woodward WR, Gliessman P, Boucher B, Nutt
JG. L-Dopa pharmacokinetics in plasma and cisternal and lumbar
cerebrospinal fluid of monkeys. Ann Neurol 1990; 27: 495-499.
Horan PJ, Mattia A, Bilsky EJ, Weber S, Davis TP, Yamamura HI,
et al. Antinociceptive profile of biphalin, a dimeric enkephalin
analog. J Pharmacol Exp Ther 1996; 265: 1446-1454.
Jakovljevic V, Banic B, Radunovic A. The effect of aluminium
chloride upon the transition of drugs through the blood-brain
barrier into the central nervous system. Eur J Drug Metab
Pharmacokinet 1991; 16: 171-175.
Johnson AK, Gross PM. Sensory circumventricular organs and
brain homeostatic pathways. FASEB J 1993; 7: 678-686.
Kastin AJ, Akerstrom V, Pan W. Glial cell line-derived
neurotrophic factor does not enter normal mouse brain. Neurosci
Lett 2003; 340: 239-241.
Kastin AJ, Akerstrom V, Pan W. Interleukin-10 as a CNS
therapeutic: the obstacle of the blood-brain/blood-spinal cord
barrier. Mol Brain Res 2003; 114: 168-171.
Kastin AJ, Banks WA, Zadina JE, Graf MV. Minireview: Brain
peptides: the dangers of constricted nomenclatures. Life Sci 1983;
32: 295-301.
Kastin AJ, Plotnikoff NP, Sandman CA, Spirtes MA, Kostrzewa
RM, Paul SM, et al. The effects of MSH and MIF on the brain. In:
Stumpf WE, Grant LD, eds. Anatomical Neuroendocrinology.
Basel, Karger 1975; 290-297.
Kelley KW, Bluthe RM, Dantzer R, Zhou J-H, Shen W-H, Johnson
RW, et al. Cytokine-induced sickness behavior. Brain Behavior
and Immunity 2003; 17: S112-S118.
Kida S, Pantazis A, Weller RO. CSF drains directly from the
subarachnoid space into nasal lymphatics in the rat. Anatomy,
histology and immunological significance. Neuropathol Appl
Neurobiol 1993; 19: 480-488.
Kim YS, Lee MH, Wisniewski HM. Aluminum induced reversible
change in permeability of the blood-brain barrier to [14C]sucrose.
Brain Res 1986; 377: 286-291.
Knopf PM, Cserr HF, Nolan SC, Wu TY, Harling-Berg CJ.
Physiology and immunology of lymphatic drainage of interstitial
and cerebrospinal fluid from the brain. Neuropathology and
Applied Neurobiology 1995; 21: 175-180.
Kolaczynski JW, Considine RV, Ohannesian J, Marco C,
Opentanova I, Nyce MR, et al. Responses of leptin to short-term
fasting and refeeding in humans: A link with ketogenesis but not
ketones themselves. Diabetes 1996; 45: 1511-1515.
Komaki G, Arimura A, Koves K. Effect of intravenous injection of
IL-1β on PGE2 levels in several brain areas as determined by
microdialysis. Am J Physiol 1992; 262: E246-E251.
Kozlowski GP, Sterzl I, Nilaver G. Localization patterns for
immunoglobulins and albumins in the brain suggest diverse
mechanisms for their transport across the blood-brain barrier
(BBB). In: Ermisch A, Landgraf R, Rühle HJ, eds. Progress in
Brain Research. Amsterdam, Elsevier 1992; 149-154.
Krisch B. The functional and structural borders between the CSFand blood-dominated milieus in the choroid plexuses and the area
postrema of the rat. Cell Tissue Res 1986; 245: 101-115.
Current Pharmaceutical Design, 2005, Vol. 11, No. 8 983
[81]
[82]
[83]
[84]
[85]
[86]
[87]
[88]
[89]
[90]
[91]
[92]
[93]
[94]
[95]
[96]
[97]
[98]
[99]
[100]
[101]
[102]
[103]
Krisch B, Leonhardt H. Relations between leptomeningeal
compartments and the neurohemal regions of circumventricular
organs. Biomed Res 1989; 10 (Suppl 3): 155-168.
Krueger JM, Obal FJ, Fang J, Kubota T, Taishi P. The role of
cytokines in physiological sleep regulation. Ann NY Acad Sci
2001; 933: 211-221.
Larson SJ, Dunn AJ. Behavioral effects of cytokines. Brain,
Behavior, and Immunity 2001; 15: 371-387.
Loy R, Talialatela G, Angelucci L, Heyer D, Perez-Polo R.
Regional CNS uptake of blood-borne nerve growth factor. J
Neurosci Res 1994; 39: 339-346.
Luheshi GN, Gay J, Rothwell NJ. Circulating IL-6 is transported
into the brain via a saturable transport mechanism in the rat. Br J
Pharmacol 1994; 112: 637P.
Male D. The blood-brain barrier - No barrier to a determined
lymphocyte. In: Greenwood J, Begley DJ, Segal MB, eds. New
Concepts of a Blood-Brain Barrier. New York, Plenum Press.
1995; 311-314.
Maness LM, Banks WA, Zadina JE, Kastin AJ. Selective transport
of blood-borne interleukin-1α into the posterior division of the
septum of the mouse brain. Brain Res 1995; 700: 83-88.
Maness LM, Banks WA, Zadina JE, Kastin AJ. Periventricular
penetration and disappearance of icv Tyr-MIF-1, DAMGO,
tyrosine, and albumin. Peptides 1996; 17: 247-250.
Maness LM, Kastin AJ, Banks WA. Relative contributions of a
CVO and the microvascular bed to delivery of blood-borne IL-1α
to the brain. Am J Physiol 1998; 275: E207-E212.
Maness LM, Kastin AJ, Farrell CL, Banks WA. Fate of leptin after
intracerebroventricular injection into the mouse brain.
Endocrinology 1998; 139: 4556-4562.
Marvel FA, Chen C-C, Badr N, Gaykema RPA, Goehler LE.
Reversible inactivation of the dorsal vagal complex blocks
lipopolysaccharide-induced social withdrawal and c-Fos expression
in central autonomic nuclei. Brain, Behavior, and Immunity 2003;
in press:
McLay RN, Kastin AJ, Zadina JE. Passage of interleukin-1-beta
across the blood-brain barrier is reduced in aged mice: A possible
mechanism for diminished fever in aging. Neuroimmunomodulation 2000; 8: 148-153.
McLay RN, Kimura M, Banks WA, Kastin AJ. Granulocytemacrophage colony-stimulating factor crosses the blood-brain and
blood-spinal cord barriers. Brain 1997; 120: 2083-2091.
Megyeri P, Abraham CS, Temesvari P, Kovacs J, Vas T, Speer CP.
Recombinant human tumor necrosis factor alpha constricts pial
arterioles and increases blood-brain barrier permeability in
newborn piglets. Neurosci Lett 1992; 148: 137-140.
Middleton J, Neil S, Wintle J, Clark-Lewis I, Moore H, Lam C, et
al. Transcytosis and surface presentation of IL-8 by venular
endothelial cells. Cell 1997; 91: 385-395.
Mizushima H, Banks WA, Dohi K, Shioda S, Matsumoto K. Effect
of cardiac arrest on brain weight and the permeability of the bloodbrain barrier and blood-spinal cord barrier to albumin and tumor
necrosis factor-α. Life Sci 1999; 20: 2127-2134.
Moinuddin A, Morley JE, Banks WA. Regional variations in the
transport of interleukin-1α across the blood-brain barrier in ICR
and aging SAMP8 mice. Neuroimmunomodulation 2000; 8: 165170.
Mondor I, Ugolini S, Sattentau QJ. Human immunodeficiency
virus type 1 attachment to HeLa CD4 cells is CD4 independent and
gp120 dependent and requires cell surface heparans. J Virol 1998;
72: 3623-3634.
Morganti-Kossman MC, Lenzlinger PM, Hans V, Stahel P, Csuka
E, Ammann E, et al. Production of cytokines following brain
injury: beneficial and deleterious for the damaged tissue. Molecular
Psychiatry 1997; 2: 133-136.
Morley JE, Farr SA, Kumar VB, Banks WA. Alzheimer's disease
through the eye of a mouse: Acceptance lecture for the 2001 Gayle
A. Olson and Richard D. Olson prize. Peptides 2002; 23: 589-599.
Morley JE, Kumar VB, Bernardo AF, Farr SA, Uezu K, Tumosa N,
et al. β-Amyloid precursor polypeptide in SAMP8 mice affects
learning and memory. Peptides 2000; 21: 1761-1767.
Muldoon Ll, Pagel MA, Kroll RA, Roman-Goldstein S, Jones RS,
Neuwelt EA. A physiological barrier distal to the anatomical bloodbrain barrier in a model of transvascular delivery. 1999;
Osburg B, Peiser C, Domling D, Schomburg L, Ko YT, Voight K,
Bickel U. Effect of endotoxin on expression of TNF receptors and
984
[104]
[105]
[106]
[107]
[108]
[109]
[110]
[111]
[112]
[113]
[114]
[115]
[116]
[117]
[118]
[119]
[120]
[121]
[122]
[123]
[124]
[125]
[126]
[127]
[128]
Current Pharmaceutical Design, 2005, Vol. 11, No. 8
transport of TNF-alpha at the blood-brain barrier of the rat. Am J
Physiol 2002; 283: E899-E908.
Pan W, Banks WA, Fasold MB, Bluth J, Kastin AJ. Transport of
brain-derived neurotrophic factor across the blood-brain barrier.
Neuropharmacology 1998; 37: 1553-1561.
Pan W, Banks WA, Kastin AJ. BBB permeability to ebiratide and
TNF in acute spinal cord injury. Exp Neurol 1997; 146: 367-373.
Pan W, Banks WA, Kastin AJ. Permeability of the blood-brain
barrier and blood-spinal cord barriers to interferons. J
Neuroimmunol 1997; 76: 105-111.
Pan W, Banks WA, Kastin AJ. Permeability of the blood-brain
barrier to neurotrophins. Brain Res 1998; 788: 87-94.
Pan W, Banks WA, Kennedy MK, Gutierrez EG, Kastin AJ.
Differential permeability of the BBB in acute EAE: enhanced
transport of TNF-α. Am J Physiol 1996; 271: E636-E642.
Pan W, Cornelissen G, Halberg F, Kastin AJ. Selected
contributions: Circadian rhythm of tumor necrosis factor-alpha
uptake into mouse spinal cord. J Appl Physiol 2002; 92: 13571362.
Pan W, Kastin AJ. Entry of EGF into brain is rapid and saturable.
Peptides 1999; 20: 1091-1098.
Pan W, Kastin AJ. Changing the chemokine gradient: CINC1
crosses the blood-brain barrier. J Neuroimmunol 2001; 115: 64-70.
Pan W, Kastin AJ. Increase in TNF alpha transport after SCI is
specific for time, region, and type of lesion. Exp Neurol 2001; 170:
357-363.
Pan W, Kastin AJ. TNF α transport across the blood-brain barrier is
abolished in receptor knockout mice. Exp Neurol 2002; 174: 193200.
Pan W, Kastin AJ. Transport of cytokines and neurotrophins across
the blood-brain barrier and their regulation after spinal cord injury.
In: Sharma HS, Westman J, eds. Blood-Spinal Cord and Brain
Barriers in Health and Disease. Amsterdam, Elsevier 2004; 395407.
Pan W, Kastin AJ, Brennan JM. Saturable entry of leukemia
inhibitory factor from blood to the central nervous system. J
Neuroimmunol 2000; 106: 172-180.
Pan W, Kastin AJ, Maness LM, Brennan JM. Saturable entry of
ciliary neurotrophic factor into the brain. Neurosci Lett 1999; 263:
69-71.
Pan W, Kastin AJ, Rigai T, McLay R, Pick CG. Increased
hippocampal uptake of tumor necrosis factor alpha and behavioral
changes in mice. Exp Brain Res 2003; 149: 195-199.
Pan W, Vallance K, Kastin AJ. TGFα and the blood-brain barrier:
accumulation in cerebral vasculature. Exp Neurol 1999; 160: 454459.
Pan W, Zadina JE, Harlan RE, Weber JT, Banks WA, Kastin AJ.
Tumor necrosis factor-α: a neuromodulator in the CNS. Neurosci
Biobehav Rev 1997; 21: 603-613.
Pan W, Zhang L, Liao J, Csernus B, Kastin AJ. Selective increase
in TNF alpha permeation across the blood-spinal cord barrier after
SCI. J Neuroimmunol 2003; 134: 111-117.
Peruzzo B, Pastor FE, Blazquez JL, Schobitz K, Pelaez B, Amat P,
et al. A second look at the barriers of the medial basal
hypothalamus. Exp Brain Res 2000; 132: 10-26.
Plotkin SR, Banks WA, Kastin AJ. Comparison of saturable
transport and extracellular pathways in the passage of interleukin1α across the blood-brain barrier. J Neuroimmunol 1996; 67: 4147.
Plotkin SR, Banks WA, Maness LM, Kastin AJ. Differential
transport of rat and human interleukin-1α across the blood-brain
barrier and blood-testis barrier in rats. Brain Res 2000; 881: 57-61.
Poduslo JF, Curran GL. Permeability at the blood-brain barrier and
blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT3, BDNF. Mol Brain Res 1996; 36: 280-286.
Pollay M, Davson H. The passage of certain substances out of the
cerebrospinal fluid. Brain 1963; 86: 137-150.
Preston E, Hynie I. Transfer constants for blood-brain barrier
permeation of the neuroexcitatory shellfish toxin, domoic acid. Can
J Neurol Sci 1991; 18: 39-44.
Pugh CR, Fleshner M, Watkins LR, Maier SF, Rudy JW. The
immune system and memory consolidation: a role for the cytokine
IL-1β. Neurosci Biobehav Rev 2001; 25: 29-41.
Quagliarello VJ, Wispelwey B, Long J, Scheld WM. Recombinant
human interleukin-1 induces meningitis and blood-brain barrier
William A. Banks
[129]
[130]
[131]
[132]
[133]
[134]
[135]
[136]
[137]
[138]
[139]
[140]
[141]
[142]
[143]
[144]
[145]
[146]
[147]
[148]
[149]
[150]
[151]
[152]
injury in the rat: characterization and comparison with tumor
necrosis factor. J Clin Invest 1991; 87: 1360-1366.
Reese TS, Brightman MW. Similarity in structure and permeability
to peroxidase of epithelia overlying fenestrated cerebral capillaries.
Anat Record 1968; 160: 414.
Reese TS, Karnovsky MJ. Fine structural localization of a bloodbrain barrier to exogenous peroxidase. J Cell Biol 1967; 34: 207217.
Rethelyi M. Diffusional barrier around the hypothalamic arcuate
nucleus in the rat. Brain Res 1984; 307: 355-358.
Reyes TM, Fabry Z, Coe CL. Brain endothelial cell production of a
neuroprotective cytokine, interleukin-6, in response to noxious
stimuli. Brain Res 1999; 851: 215-220.
Richards JG. Permeability of intercellular junctions in brain
epithelia and endothelia to exogenous amine: cytochemical
localization of extracellular 5-hydroxydopamine. J Neurocytol
1978; 7: 61-70.
Rosenberg GA, Estrada EY, Dencoff JE, Stetler-Stevenson WG.
Tumor necrosis factor-α-induced gelatinase B causes delayed
opening of the blood-brain barrier: an expanded therapeutic
window. Brain Res 1995; 703: 151-155.
Ross JF, Broadwell RD, Poston MR, Lawhorn GT. Highest brain
bismuth levels and neuropathology are adjacent to fenestrated
blood vessels in mouse brain after intraperitoneal dosing of
bismuth subnitrate. Toxicol Appl Pharmacol 1994; 124: 191-200.
Saris SC, Rosenberg SA, Friedman RB, Rubin JT, Barba D,
Oldfield EH. Penetration of recombinant interlukin-2 across the
blood-cerebrospinal fluid barrier. J Neurosurg 1988; 69: 29-34.
Schluesener H, Meyermann R. Neutrophilic defensins penetrate the
blood-brain barrier. J Neurosci Res 1995; 42: 718-723.
Schwarze SR, Ho A, Vocero-Akbani A, Dowdy SF. In vivo protein
transduction: delivery of a biologically active protein into the
mouse. Science 1999; 285: 1569-1572.
Schweighardt B, Atwood WJ. Virus receptors in the human central
nervous system. J Neurovirol 2001; 7: 187-195.
Shafer RA, Murphy S. Activated astrocytes induce nitric oxide
synthase-2 in cerebral endothelium via tumor necrosis factor alpha.
GLIA 1997; 21: 370-379.
Smith QR, Momma S, Aoyagi M, Rapoport SI. Kinetics of neutral
amino acid transport across the blood-brain barrier. J Neurochem
1987; 49: 1651-1658.
Su GC, Arendash GW, Kalaria RN, Bjugstad KB, Mullan M.
Intravascular infusions of soluble beta-amyloid compromise the
blood-brain barrier, activate CNS glial cells and induce peripheral
hemorrhage. Brain Res 1999; 818: 105-117.
Takasato Y, Rapoport SI, Smith QR. An in situ brain perfusion
technique to study cerebrovascular transport in the rat. Am J
Physiol 1984; 247: H484-H493.
Wagner JP, Black IB, DiCicco-Bloom E. Stimulation of neonatal
and adult brain neurogenesis by subcutaneous injection of basic
fibroblast growth factor. J Neurosci 1999; 19: 6006-6016.
Waguespack PJ, Banks WA, Kastin AJ. Interleukin-2 does not
cross the blood-brain barrier by a saturable transport system. Brain
Res Bull 1994; 34: 103-109.
Widner H, Jonsson BA, Hallstadius L, Wingardh K, Strand SE,
Johansson BB. Scintigraphic method to quantify the passage from
brain parenchyma to the deep cervical lymph nodes in the rat.
European Journal of Nuclear Medicine 1987; 13: 456-461.
Williams KC, Hickey WF. Traffic of hematogenous cells through
the central nervous system. 1995;
Xaio H, Banks WA, Niehoff ML, Morley JE. Effect of LPS on the
permeability of the blood-brain barrier to insulin. Brain Res 2001;
896: 36-42.
Zabel P, Linnemann K, Schlaak M. Circadian rhythm in cytokines.
Immun Infekt 1993; 21 Suppl 1: 38-40.
Banks W A. Are the extracellular (correction of extracelluar)
pathways a conduit for the delivery of therapeutics to the brain?
Curr Pharm Design 2004; 10(12): 1365-70.
Dogrukol-Ak D, Tore F, Tuncel N. Passage of VIP/PACAP/
secretin family across the blood-brain barrier: therapeutic effects.
Curr Pharm Design 2004; 10(12): 1325-40.
Pan W, Kastin AJ. Interactions of cytokines with the blood-brain
barrier: implications for feeding. Curr Pharm Design 2003; 9(10):
827-31.