1268Biochemical 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
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
Antioxidants as inhibitors of inflammatory
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 cyto-
kines, 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, migration-
inhibitory factor; NF-κB, nuclear factor κB; NAC, N-acetylcysteine; PDI, protein disulfide-
isomerase; PMN, polymorphonuclear neutrophil; Prx, peroxiredoxin; ROS, reactive oxygen
species; TNF, tumour necrosis factor; Trx, thioredoxin.
1To whom correspondence should be addressed (email email@example.com).
in many inflammatory diseases. A molecular mechanism for
this association was first provided in 1991 with the finding
that H2O2activates the transcription factor NF-κB (nuclear
target genes, while thiol antioxidants inhibit its activation .
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 .
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 know-
ledge of the role of PMN (polymorphonuclear neutrophil)-
generated ROS in tissue damage and inflammation [3,4],
distress syndrome), which is characterized by pulmonary
inflammation . Interestingly, superoxide dismutase, soon
after its identification as an antioxidant enzyme, was
investigated as a possible anti-inflammatory drug .
Antioxidants and inflammatory cytokines:
a more complex picture
However, biological systems are complex and oversimplific-
ations seldom help. The discovery of the pro-inflammatory
role of TNF  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 . This reminded researchers that TNF is a
Th1 cytokine and therefore an important molecule in innate
immunity. Interestingly, usage of the term ‘innate immunity’
C ?The Authors Journal compilation
C ?2011 Biochemical Society Biochem. Soc. Trans. (2011) 39, 1268–1272; doi:10.1042/BST0391268