* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Thiol regulation of pro-inflammatory cytokines and innate immunity
Point mutation wikipedia , lookup
Ribosomally synthesized and post-translationally modified peptides wikipedia , lookup
Ultrasensitivity wikipedia , lookup
Biochemistry wikipedia , lookup
Mitogen-activated protein kinase wikipedia , lookup
Biochemical cascade wikipedia , lookup
Gene expression wikipedia , lookup
Silencer (genetics) wikipedia , lookup
Lipid signaling wikipedia , lookup
Ancestral sequence reconstruction wikipedia , lookup
Magnesium transporter wikipedia , lookup
Expression vector wikipedia , lookup
G protein–coupled receptor wikipedia , lookup
Signal transduction wikipedia , lookup
Paracrine signalling wikipedia , lookup
Evolution of metal ions in biological systems wikipedia , lookup
Bimolecular fluorescence complementation wikipedia , lookup
Protein structure prediction wikipedia , lookup
Interactome wikipedia , lookup
Protein purification wikipedia , lookup
Nuclear magnetic resonance spectroscopy of proteins wikipedia , lookup
Western blot wikipedia , lookup
Metalloprotein wikipedia , lookup
Two-hybrid screening wikipedia , lookup
1268 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]). C The C 2011 Biochemical Society 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 C The C 2011 Biochemical Society Authors Journal compilation 1269 1270 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 C The C 2011 Biochemical Society 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. References 1 Schreck, R., Rieber, P. and Baeuerle, P.A. (1991) Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-κB transcription factor and HIV-1. EMBO J. 10, 2247–2258 2 Zimmerman, R.J., Marafino, Jr, B.J., Chan, A., Landre, P. and Winkelhake, J.L. (1989) The role of oxidant injury in tumor cell sensitivity to recombinant human tumor necrosis factor in vivo: implications for mechanisms of action. J. Immunol. 142, 1405–1409 3 McCord, J.M. (1974) Free radicals and inflammation: protection of synovial fluid by superoxide dismutase. Science 185, 529–531 4 Johnston, Jr, R.B. and Lehmeyer, J.E. (1976) Elaboration of toxic oxygen by-products by neutrophils in a model of immune complex disease. J. Clin. Invest. 57, 836–841 5 McIntyre, Jr, R.C., Pulido, E.J., Bensard, D.D., Shames, B.D. and Abraham, E. (2000) Thirty years of clinical trials in acute respiratory distress syndrome. Crit. Care Med. 28, 3314–3331 6 Cushing, L.S., Decker, W.E., Santos, F.K., Schulte, T.L. and Huber, W. (1973) Orgotein therapy for inflammation in horses. Mod. Vet. Pract. 54, 17–21 7 Beutler, B. and Cerami, A. (1986) Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature 320, 584–588 8 Mohan, A.K., Cote, T.R., Block, J.A., Manadan, A.M., Siegel, J.N. and Braun, M.M. (2004) Tuberculosis following the use of etanercept, a tumor necrosis factor inhibitor. Clin. Infect. Dis. 39, 295–299 9 Klebanoff, S.J. (1975) Antimicrobial mechanisms in neutrophilic polymorphonuclear leukocytes. Semin. Hematol. 12, 117–142 10 Curnutte, J.T., Whitten, D.M. and Babior, B.M. (1974) Defective superoxide production by granulocytes from patients with chronic granulomatous disease. N. Engl. J. Med. 290, 593–597 11 Villa, P., Saccani, A., Sica, A. and Ghezzi, P. (2002) Glutathione protects mice from lethal sepsis by limiting inflammation and potentiating host defense. J. Infect. Dis. 185, 1115–1120 12 Ghezzi, P. (2011) Role of glutathione in immunity and inflammation in the lung. Int. J. Gen. Med. 4, 105–113 13 Fahey, R.C., Hunt, J.S. and Windham, G.C. (1977) On the cysteine and cystine content of proteins: differences between intracellular and extracellular proteins. J. Mol. Evol. 10, 155–160 14 Thornton, J.M. (1981) Disulphide bridges in globular proteins. J. Mol. Biol. 151, 261–287 15 Ghezzi, P. and Di Simplicio, P. (2007) Glutathionylation pathways in drug response. Curr. Opin. Pharmacol. 7, 398–403 16 Fratelli, M., Demol, H., Puype, M., Casagrande, S., Eberini, I., Salmona, M., Bonetto, V., Mengozzi, M., Duffieux, F., Miclet, E. et al. (2002) Identification by redox proteomics of glutathionylated proteins in oxidatively stressed human T lymphocytes. Proc. Natl. Acad. Sci. U.S.A. 99, 3505–3510 17 Meissner, F., Molawi, K. and Zychlinsky, A. (2008) Superoxide dismutase 1 regulates caspase-1 and endotoxic shock. Nat. Immunol. 9, 866–872 18 Huang, Z., Pinto, J.T., Deng, H. and Richie, Jr, J.P. (2008) Inhibition of caspase-3 activity and activation by protein glutathionylation. Biochem. Pharmacol. 75, 2234–2244 19 Ghezzi, P., Casagrande, S., Massignan, T., Basso, M., Bellacchio, E., Mollica, L., Biasini, E., Tonelli, R., Eberini, I., Gianazza, E. et al. (2006) Redox regulation of cyclophilin A by glutathionylation. Proteomics 6, 817–825 20 Hoppe, G., Talcott, K.E., Bhattacharya, S.K., Crabb, J.W. and Sears, J.E. (2006) Molecular basis for the redox control of nuclear transport of the structural chromatin protein Hmgb1. Exp. Cell Res. 312, 3526–3538 21 Reynaert, N.L., van der Vliet, A., Guala, A.S., McGovern, T., Hristova, M., Pantano, C., Heintz, N.H., Heim, J., Ho, Y.S., Matthews, D.E. et al. (2006) Dynamic redox control of NF-κB through glutaredoxin-regulated S-glutathionylation of inhibitory κB kinase β. Proc. Natl. Acad. Sci. U.S.A. 103, 13086–13091 22 Prinarakis, E., Chantzoura, E., Thanos, D. and Spyrou, G. (2008) S-glutathionylation of IRF3 regulates IRF3–CBP interaction and activation of the IFNβ pathway. EMBO J. 27, 865–875 23 Watarai, H., Nozawa, R., Tokunaga, A., Yuyama, N., Tomas, M., Hinohara, A., Ishizaka, K. and Ishii, Y. (2000) Posttranslational modification of the glycosylation inhibiting factor (GIF) gene product generates bioactive GIF. Proc. Natl. Acad. Sci. U.S.A 97, 13251–13256 24 Kim-Saijo, M., Janssen, E.M. and Sugie, K. (2008) CD4 cell-secreted, posttranslationally modified cytokine GIF suppresses Th2 responses by inhibiting the initiation of IL-4 production. Proc. Natl. Acad. Sci. U.S.A. 105, 19402–19407 25 Pineda-Molina, E., Klatt, P., Vazquez, J., Marina, A., Garcia de Lacoba, M., Perez-Sala, D. and Lamas, S. (2001) Glutathionylation of the p50 subunit of NF-κB: a mechanism for redox-induced inhibition of DNA binding. Biochemistry 40, 14134–14142 26 Qanungo, S., Starke, D.W., Pai, H.V., Mieyal, J.J. and Nieminen, A.L. (2007) Glutathione supplementation potentiates hypoxic apoptosis by S-glutathionylation of p65–NF-κB. J. Biol. Chem. 282, 18427–18436 27 Ward, N.E., Stewart, J.R., Ioannides, C.G. and O’Brian, C.A. (2000) Oxidant-induced S-glutathiolation inactivates protein kinase C-α (PKC-α): a potential mechanism of PKC isozyme regulation. Biochemistry 39, 10319–10329 28 Cruz, C.M., Rinna, A., Forman, H.J., Ventura, A.L., Persechini, P.M. and Ojcius, D.M. (2007) ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages. J. Biol. Chem. 282, 2871–2879 29 Lim, S.Y., Raftery, M.J., Goyette, J., Hsu, K. and Geczy, C.L. (2009) Oxidative modifications of S100 proteins: functional regulation by redox. J. Leukocyte Biol. 86, 577–587 30 Xie, Y., Kole, S., Precht, P., Pazin, M.J. and Bernier, M. (2009) S-glutathionylation impairs signal transducer and activator of transcription 3 activation and signaling. Endocrinology 150, 1122–1131 31 Liu, S.Y., Tsai, M.Y., Chuang, K.P., Huang, Y.F. and Shieh, C.C. (2008) Ligand binding of leukocyte integrin very late antigen-4 involves exposure of sulfhydryl groups and is subject to redox modulation. Eur. J. Immunol. 38, 410–423 C The C 2011 Biochemical Society Authors Journal compilation 1271 1272 Biochemical Society Transactions (2011) Volume 39, part 5 32 Chung, S., Sundar, I.K., Yao, H., Ho, Y.S. and Rahman, I. Glutaredoxin 1 regulates cigarette smoke-mediated lung inflammation through differential modulation of IκB kinases in mice: impact on histone acetylation. Am. J. Physiol. Lung Cell Mol. Physiol. 299, L192–L203 33 Shelton, M.D., Distler, A.M., Kern, T.S. and Mieyal, J.J. (2009) Glutaredoxin regulates autocrine and paracrine proinflammatory responses in retinal glial (Muller) cells. J. Biol. Chem. 284, 4760–4766 34 Teshigawara, K., Maeda, M., Nishino, K., Nikaido, T., Uchiyama, T., Tsudo, M., Wano, Y. and Yodoi, J. (1985) Adult T leukemia cells produce a lymphokine that augments interleukin 2 receptor expression. J. Mol. Cell Immunol. 2, 17–26 35 Rimsky, L., Wakasugi, H., Ferrara, P., Robin, P., Capdevielle, J., Tursz, T., Fradelizi, D. and Bertoglio, J. (1986) Purification to homogeneity and NH2 -terminal amino acid sequence of a novel interleukin 1 species derived from a human B cell line. J. Immunol. 136, 3304–3310 36 Tagaya, Y., Maeda, Y., Mitsui, A., Kondo, N., Matsui, H., Hamuro, J., Brown, N., Arai, K., Yokota, T., Wakasugi, H. et al. (1989) ATL-derived factor (ADF), an IL-2 receptor/Tac inducer homologous to thioredoxin; possible involvement of dithiol-reduction in the IL-2 receptor induction. EMBO J. 8, 757–764 37 Balcewicz-Sablinska, M.K., Wollman, E.E., Gorti, R. and Silberstein, D.S. (1991) Human eosinophil cytotoxicity-enhancing factor. II. Multiple forms synthesized by U937 cells and their relationship to thioredoxin/adult T cell leukemia-derived factor. J. Immunol. 147, 2170–2174 38 Hori, K., Hirashima, M., Ueno, M., Matsuda, M., Waga, S., Tsurufuji, S. and Yodoi, J. (1993) Regulation of eosinophil migration by adult T cell leukemia-derived factor. J. Immunol. 151, 5624–5630 39 Bertini, R., Howard, O.M., Dong, H.F., Oppenheim, J.J., Bizzarri, C., Sergi, R., Caselli, G., Pagliei, S., Romines, B., Wilshire, J.A. et al. (1999) Thioredoxin, a redox enzyme released in infection and inflammation, is a unique chemoattractant for neutrophils, monocytes, and T cells. J. Exp. Med. 189, 1783–1789 C The C 2011 Biochemical Society Authors Journal compilation 40 Bizzarri, C., Holmgren, A., Pekkari, K., Chang, G., Colotta, F., Ghezzi, P. and Bertini, R. (2005) Requirements for the different cysteines in the chemotactic and desensitizing activity of human thioredoxin. Antioxid. Redox. Signaling 7, 1189–1194 41 Schenk, H., Vogt, M., Droge, W. and Schulze-Osthoff, K. (1996) Thioredoxin as a potent costimulus of cytokine expression. J. Immunol. 156, 765–771 42 Pekkari, K. and Holmgren, A. (2004) Truncated thioredoxin: physiological functions and mechanism. Antioxid. Redox. Signaling 6, 53–61 43 Nakamura, H., Herzenberg, L.A., Bai, J., Araya, S., Kondo, N., Nishinaka, Y. and Yodoi, J. (2001) Circulating thioredoxin suppresses lipopolysaccharide-induced neutrophil chemotaxis. Proc. Natl. Acad. Sci. U.S.A. 98, 15143–15148 44 Ueda, S., Nakamura, T., Yamada, A., Teratani, A., Matsui, N., Furukawa, S., Hoshino, Y., Narita, M., Yodoi, J. and Nakamura, H. (2006) Recombinant human thioredoxin suppresses lipopolysaccharide-induced bronchoalveolar neutrophil infiltration in rat. Life Sci. 79, 1170–1177 45 Burke-Gaffney, A., Callister, M.E. and Nakamura, H. (2005) Thioredoxin: friend or foe in human disease? Trends Pharmacol. Sci. 26, 398–404 46 Kleemann, R., Kapurniotu, A., Frank, R.W., Gessner, A., Mischke, R., Flieger, O., Juttner, S., Brunner, H. and Bernhagen, J. (1998) Disulfide analysis reveals a role for macrophage migration inhibitory factor (MIF) as thiol-protein oxidoreductase. J. Mol. Biol. 280, 85–102 47 Di Trapani, G., Orozco, C., Cock, I. and Clarke, F. (1997) A re-examination of the association of ‘early pregnancy factor’ activity with fractions of heterogeneous molecular weight distribution in pregnancy sera. Early Pregnancy Biol. Med. 3, 312–322 Received 28 June 2011 doi:10.1042/BST0391268