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The enigmatic processing and secretion of interleukin-33

Abstract

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-1β 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-1β 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.

Introduction

In the ever-growing list of cytokines, interleukin-33 (IL-33), one of the IL-1 family members (also called IL-1F11), is a most interesting novel cytokine. This cytokine was first named in 2003 as NF-HEV (nuclear factor from high endothelial venules), as it was known to interact with nuclear chromatin in an intracrine manner.1 It was rediscovered in 2005 as the specific extracellular ligand for the orphan IL-1 receptor family member ST2, and named IL-33.2 ST2 (also known as IL-1RL1, DER4, T1 and FIT-1) belongs to the Toll-like/IL-1 receptor superfamily.3, 4, 5 It has been well documented to be the cellular marker for differentiated T helper 2 (Th2) cells6, 7 and to be expressed on mast cells.8, 9 As a nuclear factor, the intracellular functions of IL-33 remain to be further clarified, although overexpression studies suggested a role as a transcriptional repressor.10 As an extracellular cytokine, binding of IL-33 to the ST2 receptor activates nuclear factor-κB and mitogen-activated protein kinases,3, 4, 5, 11 and is involved in the polarization of T cells towards the Th2 cell phenotype2, 6, 7, 11, 12, 13, 14 and in activation of mast cells,15, 16, 17, 18, 19, 20 bosophils,14, 20, 21, 22, 23, 24 eosinophils,24, 25, 26 and natural killer cells.14, 27 IL-33 must be present extracellularly in order to play the crucial role in inflammatory, infectious and autoimmune diseases including anaphylactic shock, asthma, rheumatoid arthritis, atherosclerosis, systemic sclerosis and cardiovascular diseases.5, 11, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 However, complexities and a number of discrepancies in the processing and secretion of IL-33 have been uncovered in the accumulated data. For example, full-length 31-kDa IL-331–270 has been reported, variously, as the immature/mature or inactive/active IL-33.2, 39, 40, 41, 42, 43, 44, 45, 46 The hydrolyzing role of caspase-1 in the full-length IL-33 is also brought into question by recent findings.42, 43, 44, 45, 46 For novel insights into the biological functions of the IL-33/ST2 pathway, it is crucial to address such questions and identify possible mechanisms underlying these discrepancies. This mini review summarizes the recent progress in our understanding of how IL-33 displays a potential immunoregulatory role with a particular focus on the mechanisms relating to its processing and secretion.

Can IL-33 be secreted?

It is essential for IL-33 to be secreted or released in order to bind to the ST2 receptor although an intracrine mechanism has been reported.1, 10 However, as with the IL-1 family members IL-1β and IL-18, IL-33 lacks a classical signal sequence necessary for secretion via the endoplasmic reticulum/Golgi pathway.2, 11, 33, 42, 43 Active caspase-1 has been confirmed to be a regulator of the unconventional secretion of such proteins.47 IL-1β and IL-18 are well known to be synthesized as a biologically inactive 33-kDa pro-IL-1β and 23-kDa pro-IL-18 which reside in the cytosolic compartment and to be subsequently cleaved by caspase-1 to secrete the active 17-kDa IL-1β and 18-kDa IL-18.47, 48 IL-33 is also proposed to be synthesized as a 31-kDa pro-IL-33 and to be hydrolyzed by caspase-1 to release an active 18-kDa IL-33 via the same processing and secretion mechanism as IL-1β and IL-18.2, 39, 40, 41 However, this conclusion is currently being questioned by controversial findings showing that the full-length 31-kDa IL-33 is active and that caspase-1 cleavage is not required for IL-33 activation and secretion.42, 43, 44, 45, 46 The so-called pro-IL-331–270 does not possess a definite caspase-1 cleavage site and caspase-1 does not cleave pro-IL-33 at the proposed site in vivo. The 18-kDa IL-33112–270 that has been used as a soluble recombinant cytokine is an artificially truncated form of IL-331–270 and not a product of caspase-1 hydrolyzation.42, 43, 44 In contrast, the two caspase-1 cleavage products, IL-331–178 and IL-33179–270, do not activate ST2 and the processing by caspase-1 results in attenuation or inactivation of IL-33.42, 43, 44, 45 Instead of caspase-1, calpain, a calcium-dependent cysteine protease, has been reported to mediate the full-length IL-33 processing in vivo.49 However, a recent report shows that IL-33 can be normally released from caspase-1-deficient, caspase-8 inhibitor-treated and calpain inhibitor-treated murine macrophages.46 These observations, together with the fact that the full-length 31-kDa IL-33 is active and is not a substrate of caspase-1, indicate the major differences between IL-1β/IL-18 and IL-33.

The question, then, is, how is IL-33 secreted or released? Several groups have compared the similarities between IL-33 and another IL-1 family member IL-1α.42, 44 Like IL-33, IL-1α also displays dual actions as both an intracellular nuclear factor and an extracellular cytokine.50, 51 IL-1α precursor (pro-IL-1α) is also biologically active and capable of binding to the IL-1 receptor.52 The pro-IL-1α is not a substrate of caspase-1 but can be cleaved by calpain to release 17-kDa IL-1α.11, 53, 54, 55 As with an alarmin such as high mobility group protein-1, release of IL-1α by necrotic cells is supposed to be the major route of its production.33, 42, 43, 44, 56, 57 Therefore, IL-33 release might resemble that of pro-IL-1α and high mobility group protein-1. Lüthi et al. have confirmed that IL-33 is not a substrate of inflammatory caspase-1, -4 and -5 and can be released by necrotic cells without being inactivated. In contrast, IL-33 can be efficiently cleaved by caspase-3 and -7 at physiological concentrations within apoptotic cells, resulting in reduction of the proinflammatory activity of IL-33.42, 43 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 damage or mechanical injury.44 Accordingly, IL-33 is proposed to be released from necrotic cells as one of the alarmins but to be deleted by endogenous apoptotic caspases in cells undergoing apoptosis.42, 43, 44

Besides the known autocrine, paracrine, intracrine, juxtacrine and retrocrine mechanisms of cellular interaction with cytokines, the release by necrotic cells is another recognized way for a cytokine to display its function, which we suggest might be called ‘necrocrine’. As with IL-1α and high-mobility group protein-1, IL-33 functions both as a nuclear factor in an intracrine manner and as an extracellular ‘danger signal’ in a ‘necrocrine’ manner to alert immune system during infectious and autoimmune diseases.

Remaining questions and future perspectives

The ‘necrocrine’ pathway is a satisfying explanation for the above discrepancies relating to IL-33 processing and secretion. Just how IL-33 is released, however, remains an interesting issue for the following reasons. First, release by necrotic cells seems to be too passive for IL-33 if this is an essential route. Second, the ‘necrocrine’ pathway alone is insufficient to explain the increased levels of IL-33 in sera from patients suffering from Japanese cedar pollinosis58 and active rheumatoid arthritis.59 Third, secretion of an IL-33 of about 23–25 kDa has been reported in cardiac fibroblasts stimulated by phorbol 12-myristate 13-acetate.60 Also, over 1 ng/ml of IL-33 has been detected in the supernatants of cultured astrocytes stimulated by lipopolysaccharide and adenosine triphosphate.61 Such apparently contradictory results should be considered as an indication that processing and secretion of IL-33 is an extremely complex process. Further efforts are needed to reach a conclusion, though addressing the following issues should help clarify the situation.

First, different cell sources may result in different and even contradictory conclusions. As the number of publications using recombinant IL-33 grows, the functional properties of IL-33 are becoming well characterized. However, the cellular sources and stimulants for either up- or downregulation of IL-33 expression are still largely unknown. IL-33 is reported to be constitutively expressed by endothelial,1, 2, 62, 63 epithelial63 and smooth muscle cells.2, 34 Additionally, inducible expression of IL-33 has been described in activated macrophage,2, 46 fibroblasts and keratinocytes exposed to tumour-necrosis factor-α and IL-1β,2 astrocytes stimulated by lipopolysaccharide and adenosine triphosphate,61 and adipocytes activated by tumour-necrosis factor-α.64 IL-33 is also induced when cultured endothelial cells reach confluence and stop proliferating.62 Therefore, upon stimulation, different cell populations may secrete or release IL-33 through quite different pathways.

Second, the limitation of in vitro or in vivo system and the gap between in vitro and in vivo experiments cannot be ignored when data are interpreted. While in vitro studies are indispensable, particularly in cytokine research using cultured cells and various stimulants, it is essential to avoid the overinterpretation that often accompanies predictions of the significance of an in vitro finding. Some of the findings observed in vitro may not occur in vivo. Therefore, conclusions drawn from in vitro studies should be restricted to in vitro settings until they are confirmed in an in vivo model system.

In summary, a thorough understanding of the complexity of IL-33 processing and secretion is essential to further define the biological roles and the contributions of IL-33 in various inflammatory, infectious and autoimmune diseases.

References

  1. 1

    Baekkevold ES, Roussigné M, Yamanaka T, Johansen FE, Jahnsen FL, Amalric F et al. Molecular characterization of NF-HEV, a nuclear factor preferentially expressed in human high endothelial venules. Am J Pathol 2003; 163: 69–79.

    CAS  Article  Google Scholar 

  2. 2

    Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 2005; 23: 479–490.

    CAS  Article  Google Scholar 

  3. 3

    Boraschi D, Tagliabue A . The interleukin-1 receptor family. Vitam Horm 2006; 74: 229–254.

    CAS  Article  Google Scholar 

  4. 4

    O’Neill LA . The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress. Immunol Rev 2008; 226: 10–18.

    Article  Google Scholar 

  5. 5

    Kakkar R, Lee RT . The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nat Rev Drug Discov 2008; 7: 827–840.

    CAS  Article  Google Scholar 

  6. 6

    Löhning M, Stroehmann A, Coyle AJ, Grogan JL, Lin S, Gutierrez-Ramos JC et al. T1/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.

    Article  Google Scholar 

  7. 7

    Meisel C, Bonhagen K, Löhning M, Coyle AJ, Gutierrez-Ramos JC, Radbruch A et al. Regulation and function of T1/ST2 expression on CD4+ T cells: induction of type 2 cytokine production by T1/ST2 cross-linking. J Immunol 2001; 166: 3143–3150.

    CAS  Article  Google Scholar 

  8. 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 Chem 1996; 271: 124–129.

    CAS  Article  Google Scholar 

  9. 9

    Moritz DR, Rodewald HR, Gheyselinck J, Klemenz R . The IL-1 receptor-related T1 antigen is expressed on immature and mature mast cells and on fetal blood mast cell progenitors. J Immunol 1998; 161: 4866–4874.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Carriere V, Roussel L, Ortega N, Lacorre DA, Americh L, Aguilar L et al. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc Natl Acad Sci USA 2007; 104: 282–287.

    CAS  Article  Google Scholar 

  11. 11

    Arend WP, Palmer G, Gabay C . IL-1, IL-18, and IL-33 families of cytokines. Immunol Rev 2008; 223: 20–38.

    CAS  Article  Google Scholar 

  12. 12

    Guo L, Wei G, Zhu J, Liao W, Leonard WJ, Zhao K et al. IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells. Proc Natl Acad Sci USA 2009; 106: 13463–13468.

    CAS  Article  Google Scholar 

  13. 13

    Komai-Koma M, Xu D, Li Y, McKenzie AN, McInnes IB, Liew FY . IL-33 is a chemoattractant for human Th2 cells. Eur J Immunol 2007; 37: 2779–2786.

    CAS  Article  Google Scholar 

  14. 14

    Smithgall MD, Comeau MR, Yoon BR, Kaufman D, Armitage R, Smith DE . IL-33 amplifies both Th1- and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK cells. Int Immunol 2008; 20: 1019–1030.

    CAS  Article  Google Scholar 

  15. 15

    Allakhverdi Z, Smith DE, Comeau MR, Delespesse G . Cutting edge: the ST2 ligand IL-33 potently activates and drives maturation of human mast cells. J Immunol 2007; 179: 2051–2054.

    CAS  Article  Google Scholar 

  16. 16

    Moulin D, Donzé O, Talabot-Ayer D, Mézin F, Palmer G, Gabay C . Interleukin (IL)-33 induces the release of pro-inflammatory mediators by mast cells. Cytokine 2007; 40: 216–225.

    CAS  Article  Google Scholar 

  17. 17

    Ho LH, Ohno T, Oboki K, Kajiwara N, Suto H, Iikura M et al. IL-33 induces IL-13 production by mouse mast cells independently of IgE-FcepsilonRI signals. J Leukoc Biol 2007; 82: 1481–1490.

    CAS  Article  Google Scholar 

  18. 18

    Iikura M, Suto H, Kajiwara N, Oboki K, Ohno T, Okayama Y et al. IL-33 can promote survival, adhesion and cytokine production in human mast cells. Lab Invest 2007; 87: 971–978.

    CAS  Article  Google Scholar 

  19. 19

    Xu D, Jiang HR, Kewin P, Li Y, Mu R, Fraser AR et al. IL-33 exacerbates antigen-induced arthritis by activating mast cells. Proc Natl Acad Sci USA 2008; 105: 10913–10918.

    CAS  Article  Google Scholar 

  20. 20

    Silver MR, Margulis A, Wood N, Goldman SJ, Kasaian M, Chaudhary D . IL-33 synergizes with IgE-dependent and IgE-independent agents to promote mast cell and basophil activation. Inflamm Res 2010; 59: 207–218.

    CAS  Article  Google Scholar 

  21. 21

    Suzukawa M, Iikura M, Koketsu R, Nagase H, Tamura C, Komiya A et al. An IL-1 cytokine member, IL-33, induces human basophil activation via its ST2 receptor. J Immunol 2008; 181: 5981–5989.

    CAS  Article  Google Scholar 

  22. 22

    Schneider E, Petit-Bertron AF, Bricard R, Levasseur M, Ramadan A, Girard JP et al. IL-33 activates unprimed murine basophils directly in vitro and induces their in vivo expansion indirectly by promoting hematopoietic growth factor production. J Immunol 2009; 183: 3591–3597.

    CAS  Article  Google Scholar 

  23. 23

    Kroeger KM, Sullivan BM, Locksley RM . IL-18 and IL-33 elicit Th2 cytokines from basophils via a MyD88- and p38alpha-dependent pathway. J Leukoc Biol 2009; 86: 769–778.

    CAS  Article  Google Scholar 

  24. 24

    Pecaric-Petkovic T, Didichenko SA, Kaempfer S, Spiegl N, Dahinden CA . Human basophils and eosinophils are the direct target leukocytes of the novel IL-1 family member IL-33. Blood 2009; 113: 1526–1534.

    CAS  Article  Google Scholar 

  25. 25

    Suzukawa M, Koketsu R, Iikura M, Nakae S, Matsumoto K, Nagase H et al. Interleukin-33 enhances adhesion, CD11b expression and survival in human eosinophils. Lab Invest 2008; 88: 1245–1253.

    CAS  Article  Google Scholar 

  26. 26

    Cherry WB, Yoon J, Bartemes KR, Iijima K, Kita H . A novel IL-1 family cytokine, IL-33, potently activates human eosinophils. J Allergy Clin Immunol 2008; 121: 1484–1490.

    CAS  Article  Google Scholar 

  27. 27

    Bourgeois E, Van LP, Samson M, Diem S, Barra A, Roga S et al. The pro-Th2 cytokine IL-33 directly interacts with invariant NKT and NK cells to induce IFN-gamma production. Eur J Immunol 2009; 39: 1046–1055.

    CAS  Article  Google Scholar 

  28. 28

    Nakajima H, Takatsu K . Role of cytokines in allergic airway inflammation. Int Arch Allergy Immunol 2007; 142: 265–273.

    CAS  Article  Google Scholar 

  29. 29

    Hayakawa H, Hayakawa M, Kume A, Tominaga S . Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation. J Biol Chem 2007; 282: 26369–26380.

    CAS  Article  Google Scholar 

  30. 30

    Aoki S, Hayakawa M, Ozaki H, Takezako N, Obata H, Ibaraki N et al. ST2 gene expression is proliferation-dependent and its ligand, IL-33, induces inflammatory reaction in endothelial cells. Mol Cell Biochem 2010; 335: 75–81.

    CAS  Article  Google Scholar 

  31. 31

    Kondo Y, Yoshimoto T, Yasuda K, Futatsugi-Yumikura S, Morimoto M, Hayashi N et al. Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system. Int Immunol 2008; 20: 791–800.

    CAS  Article  Google Scholar 

  32. 32

    Pushparaj PN, Tay HK, H’ng SC, Pitman N, Xu D, McKenzie A et al. The cytokine interleukin-33 mediates anaphylactic shock. Proc Natl Acad Sci USA 2009; 106: 9773–9778.

    CAS  Article  Google Scholar 

  33. 33

    Smith DE . IL-33: a tissue derived cytokine pathway involved in allergic inflammation and asthma. Clin Exp Allergy 2010; 40: 200–208.

    CAS  Article  Google Scholar 

  34. 34

    Haraldsen G, Balogh J, Pollheimer J, Sponheim J, Küchler AM . Interleukin-33 – cytokine of dual function or novel alarmin? Trends Immunol 2009; 30: 227–233.

    CAS  Article  Google Scholar 

  35. 35

    Préfontaine D, Lajoie-Kadoch S, Foley S, Audusseau S, Olivenstein R, Halayko AJ et al. Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells. J Immunol 2009; 183: 5094–5103.

    Article  Google Scholar 

  36. 36

    Kearley J, Buckland KF, Mathie SA, Lloyd CM . Resolution of allergic inflammation and airway hyperreactivity is dependent upon disruption of the T1/ST2-IL-33 pathway. Am J Respir Crit Care Med 2009; 179: 772–781.

    CAS  Article  Google Scholar 

  37. 37

    Manetti M, Ibba-Manneschi L, Liakouli V, Guiducci S, Milia AF, Benelli G et al. The IL-1-like cytokine IL-33 and its receptor ST2 are abnormally expressed in the affected skin and visceral organs of patients with systemic sclerosis. Ann Rheum Dis 2010; in press.

  38. 38

    Miller AM, Xu D, Asquith DL, Denby L, Li Y, Sattar N et al. IL-33 reduces the development of atherosclerosis. J Exp Med 2008; 205: 339–346.

    CAS  Article  Google Scholar 

  39. 39

    Dinarello CA . An IL-1 family member requires caspase-1 processing and signals through the ST2 receptor. Immunity 2005; 23: 461–462.

    CAS  Article  Google Scholar 

  40. 40

    Li H, Willingham SB, Ting JP, Re F . Cutting edge: inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3. J Immunol 2008; 181: 17–21.

    CAS  Article  Google Scholar 

  41. 41

    Cassel SL, Joly S, Sutterwala FS . The NLRP3 inflammasome: a sensor of immune danger signals. Semin Immunol 2009; 21: 194–198.

    CAS  Article  Google Scholar 

  42. 42

    Lüthi AU, Cullen SP, McNeela EA, Duriez PJ, Afonina IS, Sheridan C et al. Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity 2009; 31: 84–98.

    Article  Google Scholar 

  43. 43

    Lamkanfi M, Dixit VM . IL-33 raises alarm. Immunity 2009; 31: 5–7.

    CAS  Article  Google Scholar 

  44. 44

    Cayrol C, Girard JP . The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc Natl Acad Sci USA 2009; 106: 9021–9026.

    CAS  Article  Google Scholar 

  45. 45

    Talabot-Ayer D, Lamacchia C, Gabay C, Palmer G . Interleukin-33 is biologically active independently of caspase-1 cleavage. J Biol Chem 2009; 284: 19420–19426.

    CAS  Article  Google Scholar 

  46. 46

    Ohno T, Oboki K, Kajiwara N, Morii E, Aozasa K, Flavell RA et al. Caspase-1, caspase-8, and calpain are dispensable for IL-33 release by macrophages. J Immunol 2009; 183: 7890–7897.

    CAS  Article  Google Scholar 

  47. 47

    Keller M, Rüegg A, Werner S, Beer HD . Active caspase-1 is a regulator of unconventional protein secretion. Cell 2008; 132: 818–831.

    CAS  Article  Google Scholar 

  48. 48

    Creagh EM, Conroy H, Martin SJ . Caspase-activation pathways in apoptosis and immunity. Immunol Rev 2003; 193: 10–21.

    CAS  Article  Google Scholar 

  49. 49

    Hayakawa M, Hayakawa H, Matsuyama Y, Tamemoto H, Okazaki H, Tominaga S . Mature interleukin-33 is produced by calpain-mediated cleavage in vivo. Biochem Biophys Res Commun 2009; 387: 218–222.

    CAS  Article  Google Scholar 

  50. 50

    Maier JA, Voulalas P, Roeder D, Maciag T . Extension of the life-span of human endothelial cells by an interleukin-1 alpha antisense oligomer. Science 1990; 249: 1570–1574.

    CAS  Article  Google Scholar 

  51. 51

    Maier JA, Statuto M, Ragnotti G . Endogenous interleukin 1 alpha must be transported to the nucleus to exert its activity in human endothelial cells. Mol Cell Biol 1994; 14: 1845–1851.

    CAS  Article  Google Scholar 

  52. 52

    Mosley B, Urdal DL, Prickett KS, Larsen A, Cosman D, Conlon PJ et al. The interleukin-1 receptor binds the human interleukin-1 alpha precursor but not the interleukin-1 beta precursor. J Biol Chem 1987; 262: 2941–2944.

    CAS  PubMed  Google Scholar 

  53. 53

    Kobayashi Y, Yamamoto K, Saido T, Kawasaki H, Oppenheim JJ, Matsushima K . Identification of calcium-activated neutral protease as a processing enzyme of human interleukin 1 alpha. Proc Natl Acad Sci USA 1990; 87: 5548–5552.

    CAS  Article  Google Scholar 

  54. 54

    Carruth LM, Demczuk S, Mizel SB . Involvement of a calpain-like protease in the processing of the murine interleukin 1 alpha precursor. J Biol Chem 1991; 266: 12162–12167.

    CAS  PubMed  Google Scholar 

  55. 55

    Kavita U, Mizel SB . Differential sensitivity of interleukin-1 alpha and -beta precursor proteins to cleavage by calpain, a calcium-dependent protease. J Biol Chem 1995; 270: 27758–27765.

    CAS  Article  Google Scholar 

  56. 56

    Eigenbrod T, Park JH, Harder J, Iwakura Y, Núñez G . Cutting edge: critical role for mesothelial cells in necrosis-induced inflammation through the recognition of IL-1 alpha released from dying cells. J Immunol 2008; 181: 8194–8198.

    CAS  Article  Google Scholar 

  57. 57

    Sakurai T, He G, Matsuzawa A, Yu GY, Maeda S, Hardiman G et al. Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 2008; 14: 156–165.

    CAS  Article  Google Scholar 

  58. 58

    Sakashita M, Yoshimoto T, Hirota T, Harada M, Okubo K, Osawa Y et al. Association of serum interleukin-33 level and the interleukin-33 genetic variant with Japanese cedar pollinosis. Clin Exp Allergy 2008; 38: 1875–1881.

    CAS  Article  Google Scholar 

  59. 59

    Matsuyama Y, Okazaki H, Tamemoto H, Kimura H, Kamata Y, Nagatani K et al. Increased levels of interleukin 33 in sera and synovial fluid from patients with active rheumatoid arthritis. J Rheumatol 2010; 37: 18–25.

    CAS  Article  Google Scholar 

  60. 60

    Sanada S, Hakuno D, Higgins LJ, Schreiter ER, McKenzie AN, Lee RT . IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system. J Clin Invest 2007; 117: 1538–1549.

    CAS  Article  Google Scholar 

  61. 61

    Hudson CA, Christophi GP, Gruber RC, Wilmore JR, Lawrence DA, Massa PT . Induction of IL-33 expression and activity in central nervous system glia. J Leukoc Biol 2008; 84: 631–643.

    CAS  Article  Google Scholar 

  62. 62

    Küchler AM, Pollheimer J, Balogh J, Sponheim J, Manley L, Sorensen DR et al. Nuclear interleukin-33 is generally expressed in resting endothelium but rapidly lost upon angiogenic or proinflammatory activation. Am J Pathol 2008; 173: 1229–1242.

    Article  Google Scholar 

  63. 63

    Moussion C, Ortega N, Girard JP . The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel ‘alarmin’? PLoS One 2008; 3: e3331.

    Article  Google Scholar 

  64. 64

    Wood IS, Wang B, Trayhurn P . IL-33, a recently identified interleukin-1 gene family member, is expressed in human adipocytes. Biochem Biophys Res Commun 2009; 384: 105–109.

    CAS  Article  Google Scholar 

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Correspondence to Zhiqing Hu.

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Zhao, W., Hu, Z. The enigmatic processing and secretion of interleukin-33. Cell Mol Immunol 7, 260–262 (2010). https://doi.org/10.1038/cmi.2010.3

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Keywords

  • Interleukin-33
  • Interleukin-1 family
  • Caspase-1
  • Intracrine
  • Necrocrine

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