Cellular & Molecular Immunology (2010) 7, 260–262 ß 2010 CSI and USTC. All rights reserved 1672-7681/10 $32.00 www.nature.com/cmi
MINI REVIEW
The enigmatic processing and secretion of interleukin-33
Weihua Zhao and Zhiqing Hu
Interleukin-33 (IL-33) is the most attractive novel cytokine identified as an IL-1 family member. IL-33 was first named NF-HEV (nuclear factor from high endothelial venules), as it was known to interact with nuclear chromatin although its exact intracellular functions are still to be clarified. IL-33 is now recognized as the specific ligand for the orphan IL-1 receptor family member ST2 and to be involved in polarization of T cells towards T helper 2 cell phenotype and in activation of mast cells, bosophils, eosinophils and natural killer cells. It is essential for IL-33 to be extracellularly released in order to bind to the ST2 receptor and consequently play a crucial role in inflammatory, infectious and autoimmune diseases. However, like the IL-1 family members, IL-1b and IL-18, IL-33 mRNA is translated without a signal sequence for secretion. Additionally, IL-33 cannot be released by the processing and secretion mechanism shared by IL-1b and IL-18 as IL-33 is not a substrate of caspase-1 and does not require proteolysis for activation. In contrast, IL-33 can be inactivated by apoptotic caspases. Accordingly, IL-33 is proposed to be released as an alarmin from necrotic cells but to be deleted during apoptosis. Besides the known autocrine, paracrine, intracrine, juxtacrine and retrocrine mechanisms of cellular interaction with cytokines, release by necrotic cells is another pathway for a cytokine to display its function, which we suggest might be called ‘necrocrine’. This mini review summarizes recent progress of how IL-33 displays potential immunoregulatory roles with a particular focus on its enigmatic production. Cellular & Molecular Immunology (2010) 7, 260–262; doi:10.1038/cmi.2010.3; published online 22 March 2010
Keywords: Interleukin-33; Interleukin-1 family; Caspase-1; Intracrine; Necrocrine
INTRODUCTION hydrolyzing role of caspase-1 in the full-length IL-33 is also brought In the ever-growing list of cytokines, interleukin-33 (IL-33), one of the into question by recent findings.42–46 For novel insights into the bio- IL-1 family members (also called IL-1F11), is a most interesting novel logical functions of the IL-33/ST2 pathway, it is crucial to address such cytokine. This cytokine was first named in 2003 as NF-HEV (nuclear questions and identify possible mechanisms underlying these discrep- factor from high endothelial venules), as it was known to interact with ancies. This mini review summarizes the recent progress in our under- nuclear chromatin in an intracrine manner.1 It was rediscovered in standing of how IL-33 displays a potential immunoregulatory role 2005 as the specific extracellular ligand for the orphan IL-1 receptor with a particular focus on the mechanisms relating to its processing family member ST2, and named IL-33.2 ST2 (also known as IL-1RL1, and secretion. DER4, T1 and FIT-1) belongs to the Toll-like/IL-1 receptor superfam- ily.3–5 It has been well documented to be the cellular marker for differ- CAN IL-33 BE SECRETED? entiated T helper 2 (Th2) cells6,7 and to be expressed on mast cells.8,9 It is essential for IL-33 to be secreted or released in order to bind to the As a nuclear factor, the intracellular functions of IL-33 remain to be ST2 receptor although an intracrine mechanism has been reported.1,10 further clarified, although overexpression studies suggested a role as a However, as with the IL-1 family members IL-1b and IL-18, IL-33 transcriptional repressor.10 As an extracellular cytokine, binding of IL- lacks a classical signal sequence necessary for secretion via the endo- 33 to the ST2 receptor activates nuclear factor-kB and mitogen-acti- plasmic reticulum/Golgi pathway.2,11,33,42,43 Active caspase-1 has been vated protein kinases,3–5,11 and is involved in the polarization of T cells confirmed to be a regulator of the unconventional secretion of such towards the Th2 cell phenotype2,6,7,11–14 and in activation of mast proteins.47 IL-1b and IL-18 are well known to be synthesized as a cells,15–20 bosophils,14,20–24 eosinophils,24–26 and natural killer biologically inactive 33-kDa pro-IL-1b and 23-kDa pro-IL-18 which cells.14,27 IL-33 must be present extracellularly in order to play the reside in the cytosolic compartment and to be subsequently cleaved by crucial role in inflammatory, infectious and autoimmune diseases caspase-1 to secrete the active 17-kDa IL-1b and 18-kDa IL-18.47,48 IL- including anaphylactic shock, asthma, rheumatoid arthritis, athero- 33 is also proposed to be synthesized as a 31-kDa pro-IL-33 and to be sclerosis, systemic sclerosis and cardiovascular diseases.5,11,28–38 hydrolyzed by caspase-1 to release an active 18-kDa IL-33 via the same However, complexities and a number of discrepancies in the proces- processing and secretion mechanism as IL-1b and IL-18.2,39–41 sing and secretion of IL-33 have been uncovered in the accumulated However, this conclusion is currently being questioned by controver- data. For example, full-length 31-kDa IL-331–270 has been reported, sial findings showing that the full-length 31-kDa IL-33 is active variously, as the immature/mature or inactive/active IL-33.2,39–46 The and that caspase-1 cleavage is not required for IL-33 activation and
Department of Microbiology and Immunology, Showa University School of Medicine, Tokyo, Japan Correspondence: Dr ZQ Hu, Department of Microbiology and Immunology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. E-mail: [email protected] Received 3 December 2009; Revised 28 December 2009; accepted 17 January 2010 The novel cytokine interleukin-33 WH Zhao and ZQ Hu 261
42–46 secretion. The so-called pro-IL-331–270 does not possess a definite IL-33 is an extremely complex process. Further efforts are needed to caspase-1 cleavage site and caspase-1 does not cleave pro-IL-33 at the reach a conclusion, though addressing the following issues should help proposed site in vivo. The 18-kDa IL-33112–270 that has been used as a clarify the situation. soluble recombinant cytokine is an artificially truncated form of IL- First, different cell sources may result in different and even contra- 42–44 331–270 and not a product of caspase-1 hydrolyzation. In contrast, dictory conclusions. As the number of publications using recombinant the two caspase-1 cleavage products, IL-331–178 and IL-33179–270,do IL-33 grows, the functional properties of IL-33 are becoming well not activate ST2 and the processing by caspase-1 results in attenuation characterized. However, the cellular sources and stimulants for either or inactivation of IL-33.42–45 Instead of caspase-1, calpain, a calcium- up- or downregulation of IL-33 expression are still largely unknown. dependent cysteine protease, has been reported to mediate the full- IL-33 is reported to be constitutively expressed by endothelial,1,2,62,63 length IL-33 processing in vivo.49 However, a recent report shows that epithelial63 and smooth muscle cells.2,34 Additionally, inducible IL-33 can be normally released from caspase-1-deficient, caspase-8 expression of IL-33 has been described in activated macrophage,2,46 inhibitor-treated and calpain inhibitor-treated murine macro- fibroblasts and keratinocytes exposed to tumour-necrosis factor-a and phages.46 These observations, together with the fact that the full-length IL-1b,2 astrocytes stimulated by lipopolysaccharide and adenosine 31-kDa IL-33 is active and is not a substrate of caspase-1, indicate the triphosphate,61 and adipocytes activated by tumour-necrosis factor- major differences between IL-1b/IL-18 and IL-33. a.64 IL-33 is also induced when cultured endothelial cells reach The question, then, is, how is IL-33 secreted or released? Several confluence and stop proliferating.62 Therefore, upon stimulation, dif- groups have compared the similarities between IL-33 and another IL-1 ferent cell populations may secrete or release IL-33 through quite family member IL-1a.42,44 Like IL-33, IL-1a also displays dual actions different pathways. as both an intracellular nuclear factor and an extracellular cyto- Second, the limitation of in vitro or in vivo system and the gap kine.50,51 IL-1a precursor (pro-IL-1a) is also biologically active and between in vitro and in vivo experiments cannot be ignored when data capable of binding to the IL-1 receptor.52 The pro-IL-1a is not a are interpreted. While in vitro studies are indispensable, particularly in substrate of caspase-1 but can be cleaved by calpain to release 17- cytokine research using cultured cells and various stimulants, it is kDa IL-1a.11,53–55 As with an alarmin such as high mobility group essential to avoid the overinterpretation that often accompanies pre- protein-1, release of IL-1a by necrotic cells is supposed to be the major dictions of the significance of an in vitro finding. Some of the findings route of its production.33,42–44,56,57 Therefore, IL-33 release might observed in vitro may not occur in vivo. Therefore, conclusions drawn resemble that of pro-IL-1a and high mobility group protein-1. from in vitro studies should be restricted to in vitro settings until they Lu¨thi et al. have confirmed that IL-33 is not a substrate of inflammat- are confirmed in an in vivo model system. ory caspase-1, -4 and -5 and can be released by necrotic cells without In summary, a thorough understanding of the complexity of IL-33 being inactivated. In contrast, IL-33 can be efficiently cleaved by cas- processing and secretion is essential to further define the biological pase-3 and -7 at physiological concentrations within apoptotic cells, roles and the contributions of IL-33 in various inflammatory, infec- 42,43 resulting in reduction of the proinflammatory activity of IL-33. tious and autoimmune diseases. Cayrol et al. have also confirmed that the full-length IL-33, which is constitutively expressed by endothelial cells in most normal human tissues, can be released into the extracellular space after endothelial cell 44 damage or mechanical injury. Accordingly, IL-33 is proposed to be 1 Baekkevold ES, Roussigne´M, Yamanaka T, Johansen FE, Jahnsen FL, Amalric F et al. released from necrotic cells as one of the alarmins but to be deleted by Molecular characterization of NF-HEV, a nuclear factor preferentially expressed in 42–44 human high endothelial venules. Am J Pathol 2003; 163:69–79. endogenous apoptotic caspases in cells undergoing apoptosis. 2 Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK et al. IL-33, an Besides the known autocrine, paracrine, intracrine, juxtacrine and interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and retrocrine mechanisms of cellular interaction with cytokines, the induces T helper type 2-associated cytokines. Immunity 2005; 23: 479–490. 3 Boraschi D, Tagliabue A. The interleukin-1 receptor family. Vitam Horm 2006; 74: release by necrotic cells is another recognized way for a cytokine to 229–254. display its function, which we suggest might be called ‘necrocrine’. As 4 O’Neill LA. The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of with IL-1a and high-mobility group protein-1, IL-33 functions both as progress. Immunol Rev 2008; 226:10–18. 5 Kakkar R, Lee RT. The IL-33/ST2 pathway: therapeutic target and novel biomarker. a nuclear factor in an intracrine manner and as an extracellular ‘danger Nat Rev Drug Discov 2008; 7: 827–840. signal’ in a ‘necrocrine’ manner to alert immune system during infec- 6Lo¨hning M, Stroehmann A, Coyle AJ, Grogan JL, Lin S, Gutierrez-Ramos JC et al. T1/ tious and autoimmune diseases. ST2 is preferentially expressed on murine Th2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for Th2 effector function. Proc Natl Acad Sci USA 1998; 95: 6930–6935. REMAINING QUESTIONS AND FUTURE PERSPECTIVES 7 Meisel C, Bonhagen K, Lo¨hning M, Coyle AJ, Gutierrez-Ramos JC, Radbruch A et al. Regulation and function of T1/ST2 expression on CD41 T cells: induction of type 2 The ‘necrocrine’ pathway is a satisfying explanation for the above cytokine production by T1/ST2 cross-linking. J Immunol 2001; 166: 3143–3150. discrepancies relating to IL-33 processing and secretion. Just how 8 Gachter T, Werenskiold AK, Klemenz R. Transcription of the interleukin-1 receptor- related T1 gene is initiated at different promoters in mast cells and fibroblasts. J Biol IL-33 is released, however, remains an interesting issue for the follow- Chem 1996; 271: 124–129. ing reasons. First, release by necrotic cells seems to be too passive for 9 Moritz DR, Rodewald HR, Gheyselinck J, Klemenz R. The IL-1 receptor-related T1 IL-33 if this is an essential route. Second, the ‘necrocrine’ pathway antigen is expressed on immature and mature mast cells and on fetal blood mast cell progenitors. J Immunol 1998; 161: 4866–4874. alone is insufficient to explain the increased levels of IL-33 in sera from 10 Carriere V, Roussel L, Ortega N, Lacorre DA, Americh L, Aguilar L et al. IL-33, the IL-1- 58 patients suffering from Japanese cedar pollinosis and active rheum- like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. atoid arthritis.59 Third, secretion of an IL-33 of about 23–25 kDa has Proc Natl Acad Sci USA 2007; 104: 282–287. 11 Arend WP, Palmer G, Gabay C. IL-1, IL-18, and IL-33 families of cytokines. Immunol been reported in cardiac fibroblasts stimulated by phorbol 12-myris- Rev 2008; 223:20–38. 60 tate 13-acetate. Also, over 1 ng/ml of IL-33 has been detected in the 12 Guo L, Wei G, Zhu J, Liao W, Leonard WJ, Zhao K et al. IL-1 family members and STAT supernatants of cultured astrocytes stimulated by lipopolysaccharide activators induce cytokine production by Th2, Th17, and Th1 cells. Proc Natl Acad Sci 61 USA 2009; 106: 13463–13468. and adenosine triphosphate. Such apparently contradictory results 13 Komai-Koma M, Xu D, Li Y, McKenzie AN, McInnes IB, Liew FY. IL-33 is a should be considered as an indication that processing and secretion of chemoattractant for human Th2 cells. Eur J Immunol 2007; 37: 2779–2786.
Cellular & Molecular Immunology The novel cytokine interleukin-33 WH Zhao and ZQ Hu 262
14 Smithgall MD, Comeau MR, Yoon BR, Kaufman D, Armitage R, Smith DE. IL-33 38 Miller AM, Xu D, Asquith DL, Denby L, Li Y, Sattar N et al. IL-33 reduces the amplifies both Th1- and Th2-type responses through its activity on human basophils, development of atherosclerosis. J Exp Med 2008; 205: 339–346. allergen-reactive Th2 cells, iNKT and NK cells. Int Immunol 2008; 20:1019–1030. 39 Dinarello CA. An IL-1 family member requires caspase-1 processing and signals 15 Allakhverdi Z, Smith DE, Comeau MR, Delespesse G. Cutting edge: the ST2 ligand IL- through the ST2 receptor. Immunity 2005; 23: 461–462. 33 potently activates and drives maturation of human mast cells. J Immunol 2007; 40 Li H, Willingham SB, Ting JP, Re F. Cutting edge: inflammasome activation by alum 179: 2051–2054. and alum’s adjuvant effect are mediated by NLRP3. J Immunol 2008; 181:17–21. 16 Moulin D, Donze´O, Talabot-Ayer D, Me´zin F, Palmer G, Gabay C. Interleukin (IL)-33 41 Cassel SL, Joly S, Sutterwala FS. The NLRP3 inflammasome: a sensor of immune induces the release of pro-inflammatory mediators by mast cells. Cytokine 2007; 40: danger signals. Semin Immunol 2009; 21: 194–198. 216–225. 42 Lu¨thi AU, Cullen SP, McNeela EA, Duriez PJ, Afonina IS, Sheridan C et al. 17 Ho LH, Ohno T, Oboki K, Kajiwara N, Suto H, Iikura M et al. IL-33 induces IL-13 Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. production by mouse mast cells independently of IgE-FcepsilonRI signals. J Leukoc Immunity 2009; 31:84–98. Biol 2007; 82: 1481–1490. 43 Lamkanfi M, Dixit VM. IL-33 raises alarm. Immunity 2009; 31:5–7. 18 Iikura M, Suto H, Kajiwara N, Oboki K, Ohno T, Okayama Y et al. IL-33 can promote 44 Cayrol C, Girard JP. The IL-1-like cytokine IL-33 is inactivated after maturation by survival, adhesion and cytokine production in human mast cells. Lab Invest 2007; 87: caspase-1. Proc Natl Acad Sci USA 2009; 106: 9021–9026. 971–978. 45 Talabot-Ayer D, Lamacchia C, Gabay C, Palmer G. Interleukin-33 is biologically active 19 Xu D, Jiang HR, Kewin P, Li Y, Mu R, Fraser AR et al. IL-33 exacerbates antigen- independently of caspase-1 cleavage. J Biol Chem 2009; 284: 19420–19426. induced arthritis by activating mast cells. Proc Natl Acad Sci USA 2008; 105: 46 Ohno T, Oboki K, Kajiwara N, Morii E, Aozasa K, Flavell RA et al. Caspase-1, caspase- 10913–10918. 8, and calpain are dispensable for IL-33 release by macrophages. J Immunol 2009; 20 Silver MR, Margulis A, Wood N, Goldman SJ, Kasaian M, Chaudhary D. IL-33 183: 7890–7897. synergizes with IgE-dependent and IgE-independent agents to promote mast cell 47 Keller M, Ru¨ egg A, Werner S, Beer HD. Active caspase-1 is a regulator of and basophil activation. Inflamm Res 2010; 59: 207–218. unconventional protein secretion. Cell 2008; 132: 818–831. 21 Suzukawa M, Iikura M, Koketsu R, Nagase H, Tamura C, Komiya A et al.AnIL-1 48 Creagh EM, Conroy H, Martin SJ. Caspase-activation pathways in apoptosis and cytokine member, IL-33, induces human basophil activation via its ST2 receptor. J immunity. Immunol Rev 2003; 193:10–21. Immunol 2008; 181: 5981–5989. 49 Hayakawa M, Hayakawa H, Matsuyama Y, Tamemoto H, Okazaki H, Tominaga S. 22 Schneider E, Petit-Bertron AF, Bricard R, Levasseur M, Ramadan A, Girard JP et al.IL- Mature interleukin-33 is produced by calpain-mediated cleavage in vivo. Biochem 33 activates unprimed murine basophils directly in vitro and induces their in vivo Biophys Res Commun 2009; 387: 218–222. expansion indirectly by promoting hematopoietic growth factor production. J 50 Maier JA, Voulalas P, Roeder D, Maciag T. Extension of the life-span of human Immunol 2009; 183: 3591–3597. endothelial cells by an interleukin-1 alpha antisense oligomer. Science 1990; 249: 23 Kroeger KM, Sullivan BM, Locksley RM. IL-18 and IL-33 elicit Th2 cytokines from 1570–1574. basophils via a MyD88- and p38alpha-dependent pathway. J Leukoc Biol 2009; 86: 51 Maier JA, Statuto M, Ragnotti G. Endogenous interleukin 1 alpha must be transported 769–778. to the nucleus to exert its activity in human endothelial cells. Mol Cell Biol 1994; 14: 1845–1851. 24 Pecaric-Petkovic T, Didichenko SA, Kaempfer S, Spiegl N, Dahinden CA. Human 52 Mosley B, Urdal DL, Prickett KS, Larsen A, Cosman D, Conlon PJ et al. The interleukin- basophils and eosinophils are the direct target leukocytes of the novel IL-1 family 1 receptor binds the human interleukin-1 alpha precursor but not the interleukin-1 member IL-33. Blood 2009; 113: 1526–1534. beta precursor. J Biol Chem 1987; 262: 2941–2944. 25 Suzukawa M, Koketsu R, Iikura M, Nakae S, Matsumoto K, Nagase H et al. Interleukin- 53 Kobayashi Y, Yamamoto K, Saido T, Kawasaki H, Oppenheim JJ, Matsushima K. 33 enhances adhesion, CD11b expression and survival in human eosinophils. Lab Identification of calcium-activated neutral protease as a processing enzyme of Invest 2008; 88: 1245–1253. human interleukin 1 alpha. Proc Natl Acad Sci USA 1990; 87: 5548–5552. 26 Cherry WB, Yoon J, Bartemes KR, Iijima K, Kita H. A novel IL-1 family cytokine, IL-33, 54 Carruth LM, Demczuk S, Mizel SB. Involvement of a calpain-like protease in the potently activates human eosinophils. J Allergy Clin Immunol 2008; 121: processing of the murine interleukin 1 alpha precursor. J Biol Chem 1991; 266: 1484–1490. 12162–12167. 27 Bourgeois E, Van LP, Samson M, Diem S, Barra A, Roga S et al. The pro-Th2 cytokine 55 Kavita U, Mizel SB. Differential sensitivity of interleukin-1 alpha and -beta precursor IL-33 directly interacts with invariant NKT and NK cells to induce IFN-gamma proteins to cleavage by calpain, a calcium-dependent protease. J Biol Chem 1995; production. Eur J Immunol 2009; 39: 1046–1055. 270: 27758–27765. 28 Nakajima H, Takatsu K. Role of cytokines in allergic airway inflammation. Int Arch 56 Eigenbrod T, Park JH, Harder J, Iwakura Y, Nu´n˜ ez G. Cutting edge: critical role for Allergy Immunol 2007; 142: 265–273. mesothelial cells in necrosis-induced inflammation through the recognition of IL-1 29 Hayakawa H, Hayakawa M, Kume A, Tominaga S. Soluble ST2 blocks interleukin-33 alpha released from dying cells. J Immunol 2008; 181: 8194–8198. signaling in allergic airway inflammation. J Biol Chem 2007; 282: 26369–26380. 57 Sakurai T, He G, Matsuzawa A, Yu GY, Maeda S, Hardiman G et al. Hepatocyte necrosis 30 Aoki S, Hayakawa M, Ozaki H, Takezako N, Obata H, Ibaraki N et al.ST2gene induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced expression is proliferation-dependent and its ligand, IL-33, induces inflammatory compensatory proliferation and liver tumorigenesis. Cancer Cell 2008; 14: 156–165. reaction in endothelial cells. Mol Cell Biochem 2010; 335:75–81. 58 Sakashita M, Yoshimoto T, Hirota T, Harada M, Okubo K, Osawa Y et al. Association of 31 Kondo Y, Yoshimoto T, Yasuda K, Futatsugi-Yumikura S, Morimoto M, Hayashi N et al. serum interleukin-33 level and the interleukin-33 genetic variant with Japanese cedar Administration of IL-33 induces airway hyperresponsiveness and goblet cell pollinosis. Clin Exp Allergy 2008; 38: 1875–1881. hyperplasia in the lungs in the absence of adaptive immune system. Int Immunol 59 Matsuyama Y, Okazaki H, Tamemoto H, Kimura H, Kamata Y, Nagatani K et al. 2008; 20: 791–800. Increased levels of interleukin 33 in sera and synovial fluid from patients with 32 Pushparaj PN, Tay HK, H’ng SC, Pitman N, Xu D, McKenzie A et al. The cytokine active rheumatoid arthritis. J Rheumatol 2010; 37:18–25. interleukin-33 mediates anaphylactic shock. Proc Natl Acad Sci USA 2009; 106: 60 Sanada S, Hakuno D, Higgins LJ, Schreiter ER, McKenzie AN, Lee RT. IL-33 and ST2 9773–9778. comprise a critical biomechanically induced and cardioprotective signaling system. J 33 Smith DE. IL-33: a tissue derived cytokine pathway involved in allergic inflammation Clin Invest 2007; 117: 1538–1549. and asthma. Clin Exp Allergy 2010; 40: 200–208. 61 Hudson CA, Christophi GP, Gruber RC, Wilmore JR, Lawrence DA, Massa PT. 34 Haraldsen G, Balogh J, Pollheimer J, Sponheim J, Ku¨chler AM. Interleukin-33 – Induction of IL-33 expression and activity in central nervous system glia. J Leukoc cytokine of dual function or novel alarmin? Trends Immunol 2009; 30: 227–233. Biol 2008; 84: 631–643. 35 Pre´fontaine D, Lajoie-Kadoch S, Foley S, Audusseau S, Olivenstein R, Halayko AJ 62 Ku¨chler AM, Pollheimer J, Balogh J, Sponheim J, Manley L, Sorensen DR et al. et al. Increased expression of IL-33 in severe asthma: evidence of expression by Nuclear interleukin-33 is generally expressed in resting endothelium but rapidly airway smooth muscle cells. J Immunol 2009; 183: 5094–5103. lost upon angiogenic or proinflammatory activation. Am J Pathol 2008; 173: 36 Kearley J, Buckland KF, Mathie SA, Lloyd CM. Resolution of allergic inflammation and 1229–1242. airway hyperreactivity is dependent upon disruption of the T1/ST2-IL-33 pathway. Am 63 Moussion C, Ortega N, Girard JP. The IL-1-like cytokine IL-33 is constitutively J Respir Crit Care Med 2009; 179: 772–781. expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel 37 Manetti M, Ibba-Manneschi L, Liakouli V, Guiducci S, Milia AF, Benelli G et al. The IL- ‘alarmin’? PLoS One 2008; 3: e3331. 1-like cytokine IL-33 and its receptor ST2 are abnormally expressed in the affected 64 Wood IS, Wang B, Trayhurn P. IL-33, a recently identified interleukin-1 gene family skin and visceral organs of patients with systemic sclerosis. Ann Rheum Dis 2010; in member, is expressed in human adipocytes. Biochem Biophys Res Commun 2009; press. 384: 105–109.
Cellular & Molecular Immunology