Download Interaction between Nutrients, Pro-Inflammatory

Clinical Science (1996) 91, 121-130 (Printed i n Great Britain)
121
Editorial Review
Interaction between nutrients, pro-inflammatory cytokines and
inflammation
Robert F. GRIMBLE
Institute of Human Nutrition, University of Southampton, Southampton, U.K.
INTRODUCTION
An invasion of the body by micro-organisms and
injury activates the immune system and brings
about widespread metabolic changes. Both phenomena are closely interrelated and form part of a
complex and co-ordinated response.The objectives
of the response are to disadvantage and destroy the
invading organism, repair damaged tissue and restore tissue function to normal.
Activation of the immune system results in the
release of a complex variety of soluble mediators
from cells of the system and hepatocytes [l-31. The
mediators include immunoglobulins, complement
proteins and cytokines. Cytokines are a large group
of peptides and proteins which are involved in
signalling between the cells of the immune system.
Cytokines include interleukins (ILs), interferons,
colony stimulating factors, tumour necrosis factors
(TNFs) and transforming growth factors. A grouping of three cytokines, IL-I, IL-6 and TNF-a, not
only mediate and modulate an enhanced level of
activity in the immune system but also cause widespread metabolic changes. They belong to a subgroup of cytokines described as pro-inflammatory
cytokines as they are key mediators of inflammation. A number of cell types produce IL-1, IL-6 and
TNF-a. These include phagocytic leucocytes, T- and
B-lymphocytes, mast cells, fibroblasts and endothelial cells [4-61. Once induced, IL-1 and TNF can
stimulate production of each other and of IL-6.
Thus, a cascade of pro-inflammatory cytokines
occurs after the initial inflammatory stimulus [7].
Subsequently, nitric oxide, hydrogen peroxide and
superoxide radicals are produced by phagocytes [S].
These oxidants also enhance cytokine production.
The production of cytokines and oxidant molecules is part of a highly effective mechanism for
creating a hostile environment for pathogens within
the body [9]. Paradoxically, the high potency of
these molecules, which are essential in the body’s
defence system, may also damage the host.
The essential nature of cytokines in recovery from
inflammatory situations is indicated by the poor
prognosis of malnourished patients who have a
reduced ability for cytokine production [lo, 111.
These patients also exhibit poor wound healing as
TNF-a is an important inducer of transforming
growth factors that play a crucial part in the process.
This review focuses on the effects of IL-1, IL-6
and TNF-a, the innate systems for protecting the
subject from the potentially pathological effects of
enhanced cytokine production and the modulatory
role which nutrients may exert on such biological
events.
CYTOKINES AND THE METABOLIC
CONSEQUENCES OF INFECTION AND INJURY
Infection is characterized by fever and wasting of
peripheral tissues. Similar changes are associated
with injury. The wasting results in loss of tissue
lipid, protein and micronutrients. Widespread metabolic changes, which are part of the wasting process,
facilitate the delivery of nutrients to the immune
system, assist repair of tissues, control cytokine
production, protect healthy tissue from the effects of
free radicals and other oxidant molecules and
remove nutrients from the bloodstream which might
assist multiplication of pathogens.
Amino acids, released by increased proteolysis in
muscle, skin and bone, provide substrates for the
synthesis of cells and soluble mediators by the
immune system. Glutamine, released from muscle,
glucose derived from increased hepatic gluconeogenesis of amino acids and oleic acid from lipolysis,
are major nutrients for cells of the system [l2, 131.
~~
Key words: amino acids, antioxidants, cytokines. fats, glutathione, inflammation, interleukin, nutrition, tumour necrosis factor, vitamin E.
Abbreviations: IL, interleukin; NF, nuclear transcription factor; PUFA, polyunsaturated fatty acid; TNF, tumour necrosis factor.
Correspondence: Professor R.F. Grimble, Institute of Human Nutrition, University of Southampton, Southampton SO16 7PX, U.K.
R. F. Grimble
I 22
METABOLIC EFFECTS
Fever Anorexia Acute phase proteins
Altered copper, zinc & iron metabolism
Enhanced antioxidant defences
Muscle proteolysir Gluconeogenesir
Nitric oxide & free radical generation
stimuli
-
Nutrients
and
Acc esso r y
D r0 d UC t S
Production
/
IMMUNE SYSTEM ACTIVATION & MODULATION
IL-2
IL-3
11-4
11-8
1
1
1
1
T-cell
proliferation
Haernatopoiesis
Ig class
switching
Chernotaxis
Fig. I. Influence of pro-inflammatory cytokines upon the immune system and on metabolism after invasion of the host
by pathogens
Zinc, an important cofactor in DNA synthesis, is
released from peripheral tissues and may subsequently support cell division within the immune
system [14]. The mechanisms underlying the metabolic changes associated with the wasting process
are complex. They involve interaction between
cytokines and the hypothalamus and the direct
effects of IL-1 and TNF-a on peripheral tissues and
liver. Increased production of glucocorticoids and
catecholamines occur due to increased activity of
the sympathetic nervous system and stimulation of
corticotrophin-releasing factor production by the
actions of cytokines on the central nervous system
[15-1 71. Catecholamines, glucocorticoids and cytokines enhance glycogenolysis and gluconeogenesis
[181. Studies in patients and experimental animals
have shown that IL-1, TNF-a and agents which
induce production of these cytokines stimulate skeletal muscle protein catabolism, increase glutamine
synthesis and enhance emux of glutamine and other
amino acids from the tissue [19-231. An increased
supply of substrate for gluconeogenesis is thus
provided from skeletal muscle. The extent to which
skin and bone provide amino acids is unclear.
However, studies in uitro have shown that TNF-a
and IL-1 cause bone resorption and inhibition of
proteoglycan synthesis in cartilage [24, 251. Bacterial lipopolysaccharide produces a marked reduction
of protein synthesis in the skin and bone of rats in
uiuo [26]. A rapid increase in plasma concentrations
of free fatty acids and triacylglycerols attached to
very-low-density and low-density lipoproteins
follows administration of IL-1 and TNF-a in uiuo.
The response is due to a combination of events
which include enhanced lipolysis in adipose tissue
and increased hepatic lipogenesis [27]. IL-1, TNF-a
and glucocorticoids are responsible for the alterations in tissue zinc concentrations that have been
observed during inflammation. The cytokines cause
decreased concentrations in plasma, muscle, skin
and bone, and an increase in liver, kidney, bone
marrow and thymus [14, 281. IL-1, TNF-a and
glucocorticoids exert a stimulatory effect upon the
synthesis of metallothionein and may be partly
responsible for the increases in tissue zinc [29]. The
changes in metallothionein facilitate a shift in body
zinc from tissues which act as a reservoir (muscle,
skin, bone) to tissues where enhanced cellular
activity occurs during inflammation (thymus, bone
marrow and liver).
Thus, IL-1 and TNF-a directly and indirectly
change metabolism to provide substrate for the
immune system from endogenous sources (Fig. 1).
Such a change of nutrient supply is important, since
anorexia, and lethargy, are among the predominant
features of infected and traumatized subjects [30].
DAMAGE TO THE HOST FROM THE
INFLAMMATORY RESPONSE TO PATHOGENS
Paradoxically, although cytokines play an important role in the response to infection and injury, they
can exert damaging and lethal effects upon the host.
Several biological events enhance cytokine production, increasing the potential for damage to the host.
Oxidant molecules up-regulate cytokine production
by activation of nuclear transcription factors such as
NFKB and NFIL-6; the factors enhance transcrip-
Modulation of cytokine biology by nutrients
tion of mRNA for IL-1 and TNF-a, and for IL-6
respectively [3 1-33]. Further enhancement of cytokine production may occur since IL-1 and TNF-a
may induce production of IL-6 and further production of themselves and of each other. Induction of
nitric oxide and other oxidant molecules from phagocytic cells by IL-1, IL-8 and TNF-a may also
cause damage to the host.
Excessive, or inappropriate production of cytokines, has been associated with morbidity and mortality in a wide range of conditions in which the
immune system has become activated. These include
sepsis, adult respiratory distress syndrome, malaria,
meningitis, cancer, cystic fibrosis, systemic lupus
erythematosus, inflammatory bowel disease, rheumatoid arthritis and asthma [34-381. Furthermore,
untimely production of pro-inflammatory cytokines
has been implicated in the pathogenesis of atherosclerosis, multiple sclerosis and Alzheimer’s disease
[39-4 11.
The deleterious effects that a propensity for
cytokine production has upon the host are evident
in a study on variable genetic elements within the
major histocompatibility complex. Gambian children who were homozygous for a variant of the
TNF-cr promoter region, which enhances TNF-a
production, had seven times the mortality rates
from cerebral malaria than children who were heterozygous [42]. In autoimmune hepatitis and pulmonary tuberculosis, similar associations between a
genetic predisposition to produce IL-1 and TNF-a,
and pathology, have been noted [43, 441.
Further damage to the host may arise from the
interaction of viruses with the mechanisms controlling cytokine production. Although IL-1 and TNF
are generally antiviral in their actions, replication of
HIV is enhanced by NFKB activation. These inflammatory stimuli which enhance IL-1 and TNF production will therefore indirectly increase replication
of the virus [45].
ENDOGENOUS MODULATORS OF
PRO-I NFLAMMATORY CYTOKlN E PRODUCTION
AND ACTIONS
When an inflammatory stimulus is encountered, a
number of metabolic and cellular events occur
which can lead to suppression and localization of
the production of cytokines and their subsequent
actions.
The observation that substances in the urine of
febrile patients inhibited cytokine actions indicated
that natural inhibitors of cytokine actions are generated during inflammation. Subsequently, a sophisticated array of control systems which modulate
production of cytokines and limit their impact, has
been identified [46]. The liver, brain, adrenal cortex
and immune system play major roles in the control
systems (Fig. 2). Natural inhibitors to IL-1 and
TNF-a are produced in response to IL-1 and TNF-
I23
mi
TNFt
G
+
-
C
+
CORTEX
t
Glucocorticoids
-
F
Fig. 2. Innate systems for controlling the production and actions of
pro-inflammatory cytokines. Stimulatory actions are indicated by plus
signs and inhibitory actions by minus signs. Abbreviation: IL-Ira,
interleukin-I receptor antagonist.
a. The inhibitor for IL-1, interleukin-1 receptor
antagonist, is produced by lymphocytes and phagocytes; its amino acid sequence is very similar to that
of IL-1 and it binds to receptors for the cytokine
without leading to cellular activation. Interleukin-1
receptor antagonist thus competes with IL-1 for
binding to receptors and decreases the sensitivity of
cells to IL-1. The inhibitor for TNF-a is the extracellular domain of TNF receptors. These domains
are shed into the circulation as soluble TNF receptors after binding of TNF-a to a small proportion of
the receptors on the surface of target tissues. The
soluble receptors compete with membraneassociated TNF-a receptors, thereby reducing cellular sensitivity to the cytokine. Interleukin-1 receptor
antagonist and soluble TNF receptors are present in
plasma in concentrations that are well in excess, in
molar terms, of concentrations of IL-1 and TNF-a,
and may thus exert major inhibitory influences on
the biological activity of the two cytokines. Soluble
forms of IL-1 receptors have been found in plasma,
indicating a further way in which tissue sensitivity
to IL-1 may be reduced [47]. In addition to specific
inhibitors for IL-1 and TNF, other cytokines downregulate IL- 1 and TNF-a production. Pre-eminent
among the inhibitory cytokines are IL-4 and IL-10.
In addition to their direct effects on IL-1 and TNF,
the inhibitory cytokines exert an indirect influence
by enhancing soluble TNF receptor and interleukin1 receptor antagonist production [47].
Control mechanisms arise from the actions
of IL-1 and TNF upon the hypothalamo-pituitary-adrenal axis. Consequently, glucocorticoids
are released and suppress cytokine production
by enhancing lipocortin production [48,49]. Glucocorticoids also participate indirectly in the
control of cytokine production. They facilitate the
release of amino acids from peripheral tissues
and, in conjunction with IL-1 and IL-6, stimulate acute phase protein production by hepatocytes [50]. Some of these proteins, such as orosomucoid, a,-macroglobulin, C-reactive protein and
R. F. Grimble
I24
Table 1. Effects of nutrients on survival of animal models in conditions involving cytokine production. +, improved survival; -, impaired
survival: NT, not tested; *, fed as a mixture. Data reproduced from [IOZ].
Nutrient
tested
Arginine
Glutamine
n-3 PUFAs
n-6 PUFAS
Vitamin C
Vitamin E
Vitamin A
Iron
Fibre
Infection/
sepsis
Burn
injury
+
+
+
+
+*
+
NT
NT
NT
NT
NT
-
+
-
+
+
+
NT
Burn
injury and
infection
NT
NT
-
Cancer
+
NT
+
+
NT
+
NT
NT
NT
NT
NT
NT
NT
NT
+
a,-antichymotrypsin, inhibit neutrophil activation
and production of superoxide radicals and TNF-cr
[ S 1-53]. Increased production of orosomucoid,
caeruloplasmin, and of glutathione, enhances antioxidant defences and limits the stimulatory effects of
oxidant molecules on cytokine production.
Acute phase proteins may also enhance cytokine
production. Lipopolysaccharide binding protein
increases the sensitivity of macrophages to endotoxin and results in enhanced TNF-a production
[54]. Local amplification of cytokine production
may also occur under the action of fibronectin
which accumulates at sites of inflammation. This
glycoprotein is highly susceptible to proteolysis. Its
fragments have been shown to stimulate fibroblast
proliferation and chemotaxis and to stimulate IL- 1
and TNF-cr production [SS].
MODULATION OF CYTOKINE BIOLOGY BY
NUTRIENTS
The metabolic aspects of inflammation, described
earlier, are mediated by a range of secondary messengers and cell signalling mechanisms, which offers
broad scope for nutritional modulation.
Cytokines may have beneficial or detrimental
effects, depending upon the context and amounts in
which they are produced. During infection they are
mostly beneficial; in cancer, chronic inflammatory
disease, or in individuals infected with HIV, they
may be detrimental. Thus, beneficial dietary manipulation of cytokine production and actions may be
designed to facilitate, enhance or suppress events,
depending upon the biological or clinical context in
which they are operating [9]. Studies using animal
models have illustrated that manipulation of the
intake of a wide range of nutrients can modulate
many deleterious effects of infective and inflammatory states (Table 1).
MODULATION OF CYTOKINE PRODUCTION AND
BIOLOGICAL EFFECTS BY FATS
Fats may exert modulatory effects by influencing
the ability of cells to produce cytokines and the
ability of target tissues to respond to cytokines. This
topic has been reviewed in detail elsewhere [56, 571.
The fatty acids in dietary fat consist of four main
types according to chemical composition. These are
saturated fatty acids, such as stearic and palmitic
acid which are found in highest concentrations in
saturated fats such as' beef fat, coconut oil and
butter; n-9 monounsaturated fatty acids, such as
oleic acid which is present in high concentrations in
butter and olive oil; n-3 polyunsaturated fatty acids
(n-3 PUFAs) such as linolenic acid, present in
soyabean oil and eicosapentaenoic acid present in
high concentrations in fish oils; and n-6 PUFAs,
such as linoleic acid which is present in high
concentrations in corn, sunflower and safflower oils.
Extensive studies have been carried out, mostly in
animal models, using a number of these fats. The
studies include observation of the effects of dietary
fat on burn injury, cytokine- and endotoxin-induced
anorexia and fever, cytokine- and endotoxin-induced
changes in visceral protein metabolism and cytokine
production from macrophages. In summary, fats
rich in n-3 PUFAs or n-9 monounsaturated fatty
acids, or poor in n-6 PUFAs, reduce responsiveness
to cytokines [57, 581. Fats rich in n-6 PUFAs exert
the opposite effect. The ability of peritoneal macrophages from rats to produce IL-1 and IL-6 in
response to TNF-cr is greatly influenced by the
dietary intake of linoleic acid and total unsaturated
fatty acid intake, respectively. IL- 1 production
increases to plateau concentrations, within a range
representing 1 4 % of dietary energy, whereas IL-6
production is positively related to unsaturated fatty
acid intake over a wider range of intakes [59].
There is a limited amount of evidence that n-6
PUFA intake may influence pro-inflammatory
cytokine production in humans. Monocytes taken
from subjects consuming a cholesterol-lowering diet,
which involved a reduction in saturated fatty acid
intake from 14.1 to 4% of dietary energy, and an
increase from 6.1 to 8.8% in n-6 PUFAs, over a 24week period, exhibited enhanced IL-1 and TNF-cr
production in response to endotoxin [60]. Furthermore, blood from smokers shows a greater propensity to produce T N F in response to endotoxin, and
smokers consuming n-6 PUFA intakes of greater
than 5% of dietary energy had 2-fold greater concentrations of C-reactive protein than smokers with
a lower intake of n-6 PUFAs [61]
Inflammatory symptoms are improved by fish oil,
or n-3 PUFAs, in diseases such as rheumatoid
arthritis, psoriasis, asthma, multiple sclerosis,
Crohn's disease and ulcerative colitis [57]. Fish oil
supplementation of the diet of patients with pancreatic cancer cachexia arrested weight loss [62].
Fish oil reduces the ability of leucocytes from
healthy subjects and rheumatoid patients to produce
IL-1, IL-6 and TNF-cr [63]. This may partly explain
the anti-inflammatory effects of fish oil. y-Linolenic
acid also has a suppressive effect on plasma concentrations of a wide range of cytokines (IL-1, IL-2,
IL-4, IL-6, TNF-(r and y-interferon) in patients with
Modulation of cytokine biology by nutrients
colorectal cancer [64]. Fish oil also confers protection in animals against the lethal effects of endotoxin, burn injury and bacterial infection [65-681.
An increasing body of evidence suggests that
aberrant cytokine production is involved in atherosclerosis [39]. The association of dietary fat intake
with atherosclerosis has been the subject of extensive studies [69]. A substantial body of evidence
suggests that the intake of saturated fat is positively
associated with atherosclerosis and coronary heart
disease [69]. However, a large proportion of the
sources of saturated fat in the diet are derived from
animal sources and contain cholesterol. Cholesterol
may enhance cytokine production. Studies in rabbits
show that mRNA expression for IL-1 and TNF in
the aorta wall, in response to an endotoxin injection, is enhanced by inclusion of cholesterol in diets
containing saturated fat [70].
Many mechanisms exist whereby fats may exert
their influence upon cytokine biology. Production of
cytokines and their cellular effects are mediated and
modulated by a number of compounds formed from
the hydrolysis of membrane phospholipids by phospholipases A, and C, and by activation of protein
kinase C. Thus, the majority of mechanisms relate
to the ability of fats to change the fatty acid
composition of phospholipids within the cell membrane, Alterations in phospholipid fatty acid composition will change the nature of substrate for the
actions of phospholipase A, and phospholipase C.
Subsequently, alterations will occur in the molecular
species of diacylglycerols and eicosanoids that are
generated when the respective phospholipases are
activated. Alterations in the proportions of phospholipid classes in the membrane, and concentrations of unsaturated fatty acids within the cell,
may modulate the activities of enzymes of the
protein kinase C family [59]. The extent to which
each of these potential mechanisms play a part in
the modulatory influences of fats on cytokine biology is at present unclear. However, when rats fed a
range of fats of differing n-6 PUFA content were
injected with endotoxin, the magnitude of liver cell
membrane phospholipid hydrolysis related positively to n-6 PUFA intake [59]. The fluidity of the
cell membrane may change as a consequence of
altered phospholipid fatty acid composition. Alterations in fluidity could, in turn, change the avidity
with which cytokines bind to receptors. Measurements of changes in macrophage and hepatocyte
membrane fluidity, in response to feeding rats a
variety of fats, suggest that an alteration in the
sensitivity of either cell to inflammatory stimuli is
not directly due to changes in bulk membrane
fluidity [59, 711.
INFLUENCE OF PROTEIN AND AMINO ACID
INTAKE ON CYTOKINE BIOLOGY
The biochemical changes that occur during
inflammation exert a large metabolic demand.
I25
Cytokines bring about major changes in protein and
amino acid metabolism, whereby amino acids are
released from peripheral tissues for nutrition of cells
of the immune system and the synthesis of acute
phase proteins and glutathione by liver. However,
the supply from the peripheral tissues may not
always match demands. It has been estimated that,
during major infections in man, the amount of
protein required to produce and maintain an
increase in circulating leucocytes and acute phase
proteins is approximately 45 g/day [72].
There may be an enhanced requirement for sulphur and related amino acids after infection and
trauma [8]. Severe trauma and infection cause large
decreases in plasma glycine, serine and taurine
concentrations. These changes may be due to
enhanced utilization of glycine, serine and the sulphur amino acids, methionine and cysteine, which
are closely related in metabolism. Many substances
produced in enhanced amounts, in response to
cytokines, are rich in these amino acids. These
include glutathione, which consists of glycine, glutamic acid and cysteine; metallothionein, which contains glycine, serine, cysteine and methionine to a
composite percentage of 56%, and a range of acute
phase proteins which contain up to 25% of these
amino acids in their structure. After surgery on
uninfected patients, a decrease in the ratio of urinary sulphate to nitrogen occurs, indicating preferential retention of sulphur amino acids in tissue
components [73]. TNF-a may play a role in the
extensive weight loss observed in patients with
cancer and AIDS. In asymptomatic HIV-infected
individuals, substantial reductions in glutathione
concentrations in plasma and lung epithelial fluid
occur, which may indicate a requirement for sulphur
amino acids that is not satisfied by diet or endogenous sources [74].
The ability to increase a,-macroglobulin in response to endogenous pyrogen in rabbits, and in
response to TNF-a and turpentine abscess in rats, is
impaired by low protein diets [75-771. In rats given
a turpentine abscess, the concentration of
a,-macroglobulin increased over a wide range of
protein intakes of various degrees of adequacy. The
ability of rats fed low protein diets to increase
serum a,-acid glycoprotein and hepatic glutathione
concentrations in response to TNF-a is enhanced by
dietary supplementation with glycine and cysteine
respectively [76].
In studies in rats given TNF-a, the partitioning of
cysteine into hepatic protein and glutathione may
depend upon the dietary sulphur amino acid intake.
At low levels of intake, incorporation of cysteine
into protein is favoured over incorporation into
glutathione, to a greater extent than at high levels
of intake [73, 781. Thus, at low intakes of sulphur
amino acids, antioxidant defences may become compromised. An insufficient intake of sulphur amino
acids will thereby exert a pro-inflammatory
influence. In protein-depleted rats given TNF-a,
I26
R. F. Grimble
increases in lung glutathione concentrations were
only possible if cysteine and methionine were added
to the diet. Infiltration of inflammatory cells into
the lung, in response to the cytokine, was noted in
the absence of these amino acids from the low
protein diet, and was prevented by their addition to
the diet [78].
The ability to maintain and enhance tissue glutathione may be of particular importance in controlling cytokine production in response to inflammatory stimuli, since the stimulatory influence of
oxidant molecules and TNF-a on NFtiB activity is
decreased by glutathione and other sulphurcontaining compounds [79, SO]. Furthermore, in
rats a non-lethal dose of T N F becomes lethal if the
ability of the animal to increase and maintain
glutathione synthesis is prevented by administration
of diethylmaleate [Sl].
Thus, production of cytokines, acute phase proteins and glutathione is influenced by the adequacy
of both protein and sulphur amino acid intake.
These observations suggest that nutritional strategies concerning the supply of amino acid substrate
to individuals responding to cytokines should go
beyond consideration of all dietary protein as
simply a provider of protein nitrogen; the amino
acid proportions in that provision should also be
taken into account.
MODULATION OF CYTOKINE BIOLOGY BY
OXIDANTS AND ANTIOXIDANT STATUS
Complex antioxidant defences exist within the
host. They are distributed in body fluids and within
various compartments of the cell. Plasma contains a
wide range of substances with antioxidant properties. These include molecules derived directly from
the diet, such as vitamin E and other tocopherols,
vitamin C, p-carotene and catechins, and proteins
and peptides, such as glutathione, caeruloplasmin,
albumin and metallothionein, which are synthesized
endogenously. Many of these substances act as
antioxidants within aqueous compartments of the
cell, although vitamin E and other tocopherols are
the predominant antioxidants within cell membranes. Superoxide dismutase, catalase and glutathione peroxidase and reductase facilitate the processing of oxidant molecules to harmless by-products.
Clearly nutrients can contribute directly and indirectly to the robustness of antioxidant defences and
thereby limit the capacity of oxidants released
during inflammation to activate nuclear transcription factors and damage tissues of the host (Fig . 3).
In this role, nutrients therefore limit pathological
aspects of the cytokine-mediated response to infection and injury.
As indicated earlier, alterations in antioxidant
status brought about by changes in tissue glutathione may change the intensity of cytokine production by modulating the interaction between oxidants
and NFtiB and NFIL-6. Micronutrient intake
influences antioxidant defences. Trace elements are
present in metallothionein (Zn), caeruloplasmin
(Cu), superoxide dismutases (Cu, Se, Zn) and glutathione peroxidase (Se). Thus, dietary copper and
zinc intake may influence antioxidant defences and
the ability of the defences to be enhanced by the
actions of cytokines.
Copper deficiency in rats impairs their ability to
increase plasma caeruloplasmin and copper-zinc
superoxide dismutase in lung, in response to the
dual stress of endotoxin injection and exposure to
high concentrations of oxygen. Likewise, the ability
of IL-1 to increase plasma concentrations of caeruloplasmin with fully functional oxidase activity is
also suppressed by copper deficiency [82]. Deficiencies in zinc impair the ability of IL-1 to induce
metallothionein synthesis in rats [83].
Iron status may influence the production of
cytokines, by its ability to catalyse free radical
formation. The production of TNF-c( by mice and
IL-1 by rats, in response to endotoxin, is suppressed
by desferrioxamine (an iron chelator) and by iron
deficiency respectively [3 1, 841. Furthermore,
inflammatory symptoms in rheumatoid arthritis are
exacerbated by intravenous iron dextran [85].
Oxidation of PUFAs, as a result of free radical
attack, leads to enhanced ethane and pentane production in respired gases. Swords et al. [86] showed
that although endotoxin injections produced no
increase in ethane production in well-fed rats, production rates doubled in animals fed a diet deficient
in selenium and vitamin E. Other cytokine-mediated
responses to inflammatory agents are also modulated by vitamin E intake. In a study in which rats
were given diets either containing no vitamin E, a
normal amount of vitamin E or four times the
normal amount for 3 weeks before injection with
endotoxin, deficient animals showed the largest
anorexic response to endotoxin, the largest increase
in orosomucoid and increased plasma IL-6 concentration [87, 881. Histological examination of the
lungs indicated that although infiltration of the
lungs by immune cells was equally intense in all
dietary groups receiving endotoxin, differences
existed in the saline-injected controls. The deficient
controls had 18 and 32% more polymorphonuclear
cells in the lungs than the controls receiving diets
containing normal or supernormal amounts of
vitamin E respectively [87]. The data suggest that
vitamin E deficiency sensitizes the animals to the
mild inflammatory stimuli encountered during daily
activities. Thus, cytokine production in response to
mild and chronic or acute and severe exposure to
inflammatory agents may be modulated when
antioxidant defences are compromised by lack of
vitamin E. A similar phenomenon may occur in
human subjects. Cigarette smoking provides a chronic inflammatory stimulus to the macrophage population in the lung. Indeed, raised plasma concentrations of acute phase protein and IL-6 have been
Modulation of cytokine biology by nutrients
Extracellular
antioxidant
defences
Cytokines
=b
I27
Vitamins C & E
Carotene
3,
Oxidant
Cell
NFKB
NFlL-6
+It
DNA transcription
HIV
replication
Acute phase
protein
synthesis
Cy to kine
synthesis
Fig. 3. Interactions between oxidants and antioxidant defences in the activation of nuclear transcription factors during inflammation. Stimulatory actions
are indicated by plus signs and inhibitory actions by minus signs. Abbreviation: SOD, superoxide dismutase.
observed in smokers, together with an enhanced
capacity of whole blood samples to produce TNF-ct
when stimulated with endotoxin [61]. In smokers,
acute phase protein concentrations correlated negatively with vitamin E intake [SS].
MODULATORY INFLUENCE OF THE AMOUNT
AND ROUTE OF NUTRIENT DELIVERY ON
CYTOKINE BIOLOGY
Anorexia is a key feature of the response to
pro-inflammatory cytokines. The question of the
extent to which correction of appetite loss by nasogastric or parenteral feeding carries risks or benefits
is important in patients with an ongoing inflammatory response. Anorexia may be an unfortunate
phenomenon associated with the metabolic changes
induced by cytokines, or it may be an attempt to
selectively avoid nutrients that might disadvantage
the response of the host to pathogens. Experimental
and observational data suggest that either possibility could be the case. Rats given IL-1 and a choice
of casein, lard or a mixture of sucrose and cornstarch, reduced intakes of the protein and fat by 51
and 68% respectively, whereas carbohydrate appetite
was unaffected [90].
Beneficial effects on immune function, morbidity
and mortality were observed in burned children
supplied with additional protein in the form of whey
protein. The unsupplemented and supplemented
diets contained 16.5 and 23% of energy as protein,
respectively. Improvements in neutrophil opsonic
index, plasma acute phase proteins, survival and
number of days with bacteraemia were noted in
children fed the whey protein supplements [9 I].
However, asymptomatic infected malnourished
children often become febrile during nutritional
rehabilitation. The appearance of fever may indicate
an enhancement of cytokine production, previously
held in check by the malnourished state [92]. In
malnourished elderly patients showing an impaired
ability to produce cytokines, dietary protein supplementation restored and enhanced production [lo].
Such an enhancement carries benefits and dangers
for the host if it is not part of a carefully coordinated metabolic response that disadvantages the
pathogen but protects the host. Indeed, enhanced
mortalities have been noted in malnourished
infected populations once nutritional supplementation is commenced [93]. Similar phenomena have
been observed in studies in animals. Mortality from
malaria and bacterial infection is modified by alter-
I28
R. F. Grimble
ations in specific amino acid and protein intake.
Mortality in rats from Plasmodium berghei malaria
was reduced by low protein diets but enhanced by
dietary supplementation with a mixture of threonine, valine, leucine and isoleucine [94]. Likewise,
mortality in guinea pigs from Escherichia coli and
Staphylococcus aureus infection was increased from
15 to 54% over a range of protein intakes, from an
inadequate 5% of total dietary energy as protein to
20% [95]. Similar deleterious effects on mortality
from bacteraemia were observed in guinea pigs
receiving increased quantities of an adequate diet.
While 62% mortality occurred when an adequate
quantity was fed (523 kJ day-' kg-I), increasing
intake to 628 or 732 kJ day- kg- resulted in 100%
mortality [96]. Enhanced cytokine production
rather than increased virulence may underlie these
paradoxical effects of dietary supplementation.
'
Although malnutrition decreases the ability to
produce cytokines, a chronic reduction in food
intake may bring about the opposite effect. Vaisman
et al. [97] showed that monocytes taken from obese
patients who received 420 kJ/day for 6 days, showed
a 3-fold enhancement in ability to produce TNF-a
in response to phytahaemagglutinin or endotoxin
stimulation in uitro compared with the response
before diet restriction. The reason for this paradox
may lie in gut physiology. Fong et al. [98] observed
the effects of 'bowel rest' on subsequent T N F production in response to endotoxin by feeding healthy
volunteers via the enteral and parenteral routes.
Peak plasma T N F concentrations were three times
greater in subjects fed parenterally than in those fed
enterally. Fong et al. suggest that the stimulatory
effect was due to an increase in bacterial translocation and endotoxin transfer into the portal circulation when the gut food content decreased. Exposure
of Kupffer cells to these inflammatory agents would
result in a low level of cytokine production that
would sensitize the volunteer's immune system,
thereby enhancing T N F production in response to
the subsequent endotoxin challenge. An oral intake
of 420kJ/day in the study of obese patients may
have been insufficient to prevent translocation and
sensitization [97]. A number of studies have shown
the clinical advantage of feeding via the enteral
rather than the parenteral route if a choice is
permitted by the condition of the patient. Part of
the effectiveness of the former route may lie in the
prevention of sensitization of cells of the immune
system within the viscera to inflammatory stimuli.
'
'
CONCLUSIONS
The essence of survival of an individual, or species, lies in the ability to prioritize physiological
processes, particularly those processes that exert a
large metabolic demand. Thus, at various times in
the life cycle, metabolic processes become focused
upon achieving growth, the construction of placenta
and foetus, the synthesis of milk components and
the repulsion of an invasion by pathogens. For the
infected individual, the marshalling of resources to
combat the infective agent takes high priority. Other
physiological processes can take precedence once
the invasion has been repelled and the damage
caused by the invader repaired.
The high priority given to combating pathogens
is necessary because of the speed with which pathogens multiply once established within the host. In
general terms, bacterial cells multiply at least 50
times as rapidly as T-cells under favourable conditions. Thus, the provision of nutrients to allow the
immune system to function correctly cannot be left
to chance. Cytokines therefore play a crucial role as
modulatory agents by which the activity of the
system is changed and metabolic activity of the host
directed towards provision of nutrients for the
system from endogenous sources. The enhanced
level of cytokines and free radical production that
follows pathogenic invasion, although designed to
combat the invader, has the potential to damage the
host. Damage, however, is limited by enhancement
of the antioxidant defences of the host and activation of systems for retaining cytokine production
within healthful confines.
As discussed earlier, previous and concurrent
nutrient intake modulate cytokine biology. Nutrients may act at many cellular locations, changing
cytokine production and altering the responsiveness
of target tissues to cytokines. Fats mainly exert a
direct influence at the level of the cell membrane by
changing phospholipid fatty acid composition. Protein and individual amino acids facilitate the widespread change in protein metabolism that occurs
during inflammation. Sulphur amino acids and
other nutrients which influence antioxidant defences
may modulate cytokine production indirectly by
modulating activation of transcription factors by
oxidant molecules produced during inflammation.
As a consequence of the nutritional modulation, the
host will experience depletion of resources and
damage which ranges from being mild and temporary in nature, to severe, chronic and lethal.
The future challenge for the clinician and scientist
will be to determine how the nature of the nutrient
cytokine interactions, identified in the experimental
context, can be employed to achieve a healthful diet
and clinical benefit [98-1021.
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