Download Thiol regulation of pro-inflammatory cytokines and innate immunity

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Biochemical Society Transactions (2011) Volume 39, part 5
Thiol regulation of pro-inflammatory cytokines
and innate immunity: protein S-thiolation as a
novel molecular mechanism
Lucia Coppo*† and Pietro Ghezzi*1
*Brighton and Sussex Medical School, Falmer, Brighton, BN1 9RY, U.K., and †Department of Neuroscience, Pharmacology Unit, University of Siena,
53100 Siena, Italy
Abstract
Inflammation or inflammatory cytokines and oxidative stress have often been associated, and thiol
antioxidants, particularly glutathione, have often been seen as possible anti-inflammatory mediators.
However, whereas several cytokine inhibitors have been approved for drug use in chronic inflammatory
diseases, this has not happened with antioxidant molecules. We outline the complexity of the role of protein
thiol–disulfide oxidoreduction in the regulation of immunity and inflammation, the underlying molecular
mechanisms (such as protein glutathionylation) and the key enzyme players such as Trx (thioredoxin) or
Grx (glutaredoxin).
Introduction
Antioxidants as inhibitors of inflammatory
cytokines
Inflammatory cytokines and oxidative stress are often
associated in the literature and have many similarities.
Both terms began being used in the early 1980s (see
http://ngrams.googlelabs.com). Both inflammatory cytokines, particularly IL (interleukin)-1 and TNF (tumour
necrosis factor), and oxidative stress have been implicated
in so many diseases that it would be difficult to find one
where neither has been involved. Both are interpreted with
an ‘axis-of-evil’ perspective, where they play a pathogenic
role, and this oversimplification has probably contributed to
the rapid diffusion of these two areas or research. However,
while in the field of inflammatory cytokines a number of
cytokine inhibitors have been developed and approved for
therapeutic use (e.g. anti-TNF and anti-IL-6 molecules in
rheumatoid arthritis and inflammatory colitis), inhibitors of
oxidative stress (antioxidants) are confined to the nebulous
area of alternative medicine and none have made the jump to
regulatory approval, despite many clinical trials and a large
number of molecules tested, a fact that cannot be explained
by a conspiracy theory.
Inflammatory cytokines and oxidative stress have more in
common than historical similarities. Increased production of
inflammatory cytokines and oxidative stress, either defined
as an increased production of ROS (reactive oxygen species)
or a decrease in the GSH/GSSG ratio, are often associated
Key words: cytokine, glutathione, immunity, inflammation, redox regulation, thioredoxin.
Abbreviations used: ARDS, acute respiratory distress syndrome; GIF, glycosylation-inhibiting
factor; Grx, glutaredoxin; IKK, inhibitor of nuclear factor κB kinase; IL, interleukin; MIF, migrationinhibitory factor; NF-κB, nuclear factor κB; NAC, N-acetylcysteine; PDI, protein disulfideisomerase; PMN, polymorphonuclear neutrophil; Prx, peroxiredoxin; ROS, reactive oxygen
species; TNF, tumour necrosis factor; Trx, thioredoxin.
1 To whom correspondence should be addressed (email [email protected]).
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Authors Journal compilation in many inflammatory diseases. A molecular mechanism for
this association was first provided in 1991 with the finding
that H2 O2 activates the transcription factor NF-κB (nuclear
factor κB) which has many inflammatory cytokines among its
target genes, while thiol antioxidants inhibit its activation [1].
Several studies have reported the inhibition of cytokine
production by many thiol antioxidants, including GSH or
NAC (N-acetylcysteine). Other studies have shown that
antioxidants protect from TNF cytotoxicity [2].
In general, there is a wide acceptance of the equation
oxidative stress = inflammation, and GSH is often regarded
as an endogenous anti-inflammatory mediator. This actually
goes back to the pre-cytokine era, and adds to earlier knowledge of the role of PMN (polymorphonuclear neutrophil)generated ROS in tissue damage and inflammation [3,4],
and particularly in sepsis-associated ARDS (acute respiratory
distress syndrome), which is characterized by pulmonary
inflammation [5]. Interestingly, superoxide dismutase, soon
after its identification as an antioxidant enzyme, was
investigated as a possible anti-inflammatory drug [6].
Antioxidants and inflammatory cytokines:
a more complex picture
However, biological systems are complex and oversimplifications seldom help. The discovery of the pro-inflammatory
role of TNF [7] led to the development of anti-TNF
antibodies, a breakthrough in the therapy of chronic
inflammatory diseases. However, a few years after U.S.
approval, in 1998, of anti-TNF antibodies for the therapy
of rheumatoid arthritis, it became clear that TNF blockade
caused increased susceptibility to infections, which in some
cases was lethal [8]. This reminded researchers that TNF is a
Th1 cytokine and therefore an important molecule in innate
immunity. Interestingly, usage of the term ‘innate immunity’
Biochem. Soc. Trans. (2011) 39, 1268–1272; doi:10.1042/BST0391268
Analysis of Free Radicals, Radical Modifications and Redox Signalling
took off almost 10 years after that of the term ‘cytokines’,
but we are now all familiar with the concept of the dual role
of innate immunity in host defence compared with tissue
damage, which translates in the concept of risk/benefit ratio
when using cytokine inhibitors.
The evolution towards a more complex concept, as
opposed to a one-way view, is indicated by the recent
diffusion of the concept of redox regulation.
Specifically in the field of innate immunity, an obvious
question would be: if antioxidants and ROS scavengers are
inhibitors of inflammation, should we expect them to inhibit
some of the mechanisms of innate immunity, thus worsening
infections? The question is not as unrealistic as it seems, as
ROS are one of the main antibacterial weapons of PMN
[9], and lack of ROS production by PMN is on the basis
of chronic granulomatous disease, characterized by increased
susceptibility to infection [10].
We have attempted to address this question using a
model of polymicrobial peritoneal sepsis induced by CLP
(caecal ligation and puncture) using as tools a GSH-depleting
agent, the GSH synthesis inhibitor BSO (buthionine-SRsulfoximine) and the GSH precursor NAC. We expected
that GSH would act as an anti-inflammatory mediator of
sepsis-induced ARDS, evaluated as PMN infiltration. In fact,
we observed that, in agreement with previous studies, GSH
depletion increased pulmonary PMN infiltrate, while NAC
decreased it. However, surprisingly, when we looked at PMN
migration at the site of infection, inflammatory infiltrate was
increased by NAC and decreased by GSH depletion. Possibly
as a result of these opposite effects on the inflammatory
infiltrate at the site of infection (the peritoneal cavity) and
in a distant organ (the lung), survival curves indicated that
GSH improved survival [11].
We concluded that GSH does not simply inhibit
inflammation, but rather acts as a regulatory mediator
[12]. The molecular basis for the regulatory action of
glutathione must be more complicated than simply acting
as an antioxidant defence by scavenging ROS.
Molecular basis for the regulatory function
of glutathione: the concept of
redox-sensitive proteins
Glutathione is not just an antioxidant (in its GSH form).
The GSH/GSSG couple also acts as a redox buffer, regulating
the redox state of ‘redox-sensitive proteins’. In fact, it has
long been thought that cysteine residues in proteins can
exist in two different forms: free (with the free thiol) or
engaged in a disulfide bond, and this is the information
that we can obtain if we look up a protein sequence
in various databases (http://www.ncbi.nlm.nih.gov/protein;
http://www.uniprot.org/). It is also thought that, in general,
cytosolic proteins have their cysteine residues mostly in the
free thiol ( − SH) state, while secreted proteins have them
oxidized as disulfides [13,14]. This is because the extracellular
environment is an oxidizing one, while the cytosol is a
Table 1 Oxidation states of protein cysteine residues
Abbreviations used: C, cysteine; G, glutathione; P, protein.
State
Structure
Free thiol
Protein–protein disulfide
P-SH
PS-SP
Glutathionylated
Cysteinylated
Sulfenic acid
PS-SG
PS-SC
P-SOH
Sulfinic acid
Sulfonic acid
Nitrosothiol
P-SO2 H
P-SO3 H
P-SNO
Note
Unstable
Irreversible?
reducing one, owing to the high concentrations of GSH and
the high GSH/GSSG ratio.
The overall concept of redox regulation is based on the fact
that many cysteine residues that, in theory (according to the
databases), are in the reduced state can in fact exist in various
oxidation states. These include: (i) inter-chain disulfides;
(ii) mixed disulfides with small molecular mass thiols (e.g.
GSH, glutathionylation or with cysteine, cysteinylation);
(iii) S-nitrosylation; (iv) oxidation to sulfinic, sulfenic or
sulfonic acids (Table 1). All these oxidations are reversible
(with the possible exception of sulfonic acids), and this
reversibility makes these modifications likely mechanisms
of regulation of protein function, similar to other posttranslational modifications such as phosphorylation.
Whether a given cysteine residue in a protein is susceptible
to these modifications is determined by various factors,
including its reactivity (which depends on the neighbouring
amino acids) and its accessibility (for instance, reaction with
GSH or GSSG to form a glutathionylated protein will have a
different accessibility requirement than reaction with H2 O2
to form a sulfinic acid [15]). This is different from protein
phosphorylation, which is, in large part, sequence-specific.
Protein thiol–disulfide oxidoreductases:
key players in redox regulation
In analogy with protein phosphorylation, which is regulated
by protein kinases and phosphatases, cysteine residues can be
oxidoreduced by a number of enzymes in the protein thiol–
disulfide oxidoreductase family (Table 2). These include: Trx
(thioredoxin), Grx (glutaredoxin) and PDI (protein disulfideisomerase). Prx (peroxiredoxin) can detoxify peroxides by
oxidizing Trx. These enzymes, particularly Trx, can catalyse
several reactions with many substrates in general, but the
reader should bear in mind that this is an oversimplification.
Trx, Grx and Prx are considered antioxidant enzymes (which
maintain proteins in the reduced state), while PDI is often
considered an oxidant, important for the formation of
structural disulfides in protein folding. Trx, Grx and PDI
all have a CXXC-motif active site (CGPC in Trx, CPYC
in Grx, CGHC in PDI) where the two cysteine residues
form a transient disulfide as a reaction intermediate. Grx
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Biochemical Society Transactions (2011) Volume 39, part 5
Table 2 Protein thiol-disulfide oxidoreductases
Table 3 Proteins of relevance to immunity undergoing
For most of these enzymes, several isoforms exist. SOX, thiol oxidase;
Srx, sulfiredoxin.
glutathionylation.
Abbreviations used: HMGB1, high-mobility group protein box 1; IRF,
interferon regulatory factor; PI3K, phosphoinositide 3-kinase; PTEN,
Enzyme
Activity/function
Trx
Reduces protein disulfides in general
Grx
Prx
PDI
Reduces glutathionylated proteins
Oxidizes Trx
Oxidizes protein thiols, e.g. in folding
Protein
Effect
Reference(s)
Caspase 1
Inhibition
[17]
SOX
Srx
Oxidizes protein thiols, e.g. in folding
Reduces sulfinic acids
Caspase 3
Cyclophilin A
HMGB1
Inhibition
Unknown
Nucleocytoplasmic
[18]
[19]
[20]
IKKβ
IRF3
transport
Inhibition
Inhibits transcriptional
[21]
[22]
and Trx in particular can reduce glutathionylated proteins
at the expense of another reducing agent (GSH) catalysing
the thiol–disulfide exchange reaction from right to left:
phosphatase and tensin homologue deleted on chromosome 10; STAT,
signal transducer and activator of transcription; VLA, very late antigen.
MIF/GIF*
Protein − SH + GSSG → protein − SG + GSH
Other relevant enzymes in this context are Srx
(sulfiredoxin) that reduces sulfinic acids to free thiols, and
SOXs (thiol oxidases; also with a CXXC motif), which
catalyse the formation of protein disulfides.
Protein S-thiolation in regulation of
immunity
Since our first study in human T-lymphocytes [16], many
applied proteomic techniques (‘redox proteomics’) have been
used to identify proteins undergoing glutathionylation, and
hundreds have been identified to date. Table 3 lists some of
those relevant to immunity.
From what is discussed above, it is clear that GSH
is not only a free radical scavenger, but also a signalling
molecule. Glutathionylation can be either anti-inflammatory
or pro-inflammatory depending on the protein targeted.
One example of this is provided by the effect of
glutathionylation of various proteins in the NF-κB pathway.
Glutathionylation of p65–NF-κB leads to its inactivation
[26] and glutathionylation of p50–NF-κB inhibits DNA
binding [25], and thus oxidation (glutathionylation) should
be anti-inflammatory. On the other hand, glutathionylation
inhibits the IKKβ (inhibitor of NF-κB kinase β), which
will result in a pro-inflammatory effect of its oxidation
[21]. To confirm the contrasting role of glutathionylation,
endogenous Grx can both decrease [32] or augment [21,33]
production of inflammatory cytokines, depending on the
experimental model.
Protein thiol–disulfide oxidoreductases in
immunity
While the main role of protein thiol–disulfide oxidoreductases is intracellularly as redox enzymes, they can also
be secreted and have extracellular functions. The enzyme in
this family that is most known to immunologists is probably
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Authors Journal compilation NF-κB, p50 and p65
PKC (protein kinase C)
activity
Gain of function,
inhibits IgE
production
Inhibition
Inhibition
[23,24]
[25,26]
[27]
PTEN
Inactivation, leading
to PI3K activation
[28]
S100
STAT3
Various
Inhibited IL-6
signalling
[29]
[30]
VLA-4 (integrin α4β1)
Modulation of ligand
binding
[31]
*Cysteinylation.
Trx. As early as 1985, Yodoi and co-workers identified a new
cytokine that they called ADF (ATL-derived factor), which
augmented the expression of the IL-2 receptor [34] and was
identical with a factor thought to be an isoform of IL-1 [35].
These were finally identified as Trx [36]. Subsequently various
activities of Trx on leucocytes were reported. These include
activation of eosinophil cytotoxicity [37] and migration [38],
chemotactic activity towards monocytes, neutrophils and
lymphocytes [39,40] and co-stimulation of TNF production
in monocytes [41]. Trx can also be secreted as a C-terminally
truncated form (Trx80), which induces IL-12 production and
CD14 expression in monocytes [42]. It should be mentioned,
however, that some of the immunological actions of Trx are
independent of the redox action, as they are also present in
redox-dead mutants lacking the CXXC motif [42]. Administration of Trx inhibits leucocyte migration in vivo [43,44],
possibly by a mechanism of desensitization related to its
chemotactic action [40], and is elevated in several infective or
inflammatory pathological conditions (see [45] for a review).
The mechanism underlying the extracellular actions of Trx,
and possibly other redox-active cytokines, are not yet understood, as no specific receptors have been identified to date.
One of the earliest discovered cytokines, macrophage MIF
(migration-inhibitory factor) has a CXXC Trx-like domain
that is essential for its activity [46]. When secreted, MIF can be
Analysis of Free Radicals, Radical Modifications and Redox Signalling
cysteinylated, acquiring novel immunological functions, and
is identical with a factor once known as GIF (glycosylationinhibiting factor) [23,24]. Trx is also a component of
the elusive immunosuppressive molecule termed ‘early
pregnancy factor’ [47]. Finally, S100 calgranulins can undergo
glutathionylation, thus regulating their diverse cytokine-like
activities in the context of inflammation (for a comprehensive
review, see [29]).
Conclusions and limits of the present
review
The concept of redox regulation is clearly an evolution
of the concept of oxidative stress and is obviously more
complex. It is not ‘black-and-white’, but introduces shades
of grey. Translating this into the field of innate immunity
and inflammation, this complexity probably explains why
antioxidants are not good drugs, as they affect a number
of regulatory mechanisms. On the other hand, this does
by no means imply that GSH depletion is not detrimental.
In fact, GSH is doubly important, not only as an
antioxidant, but also as a signalling molecule. This probably
explains why glutathione (both GSH and GSSG) depletion
is often associated with an increased susceptibility to
infection (defective immunity) or inflammation (exaggerated
immunity) [12].
Finally, just for the reader to be aware, we should mention
that the present mini-review did not discuss S-nitrosylation,
which is clearly another form of oxidation of protein thiols
of great importance in inflammation and immunity. Also we
have not discussed the relevance of protein thiols in HIV.
Funding
P.G. is supported by the Brighton and Sussex Medical School and the
RM Phillips Charitable Trust.
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Received 28 June 2011
doi:10.1042/BST0391268