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.
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.
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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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