IL‐1, IL‐18, and IL‐33 families of cytokines

Abstract

Summary: The interleukin-1 (IL-1), IL-18, and IL-33 families of cytokines are related by mechanism of origin, receptor structure, and signal transduction pathways utilized. All three cytokines are synthesized as precursor molecules and cleaved by the enzyme caspase-1 before or during release from the cell. The NALP-3 inflammasome is of crucial importance in generating active caspase-1. The IL-1 family contains two agonists, IL-1a and IL-1b, a specific inhibitor, IL-1 receptor antagonist (IL1Ra), and two receptors, the biologically active type IL-1R and inactive type II IL-1R. Both IL-1RI and IL-33R utilize the same interacting accessory protein (IL-1RAcP). The balance between IL-1 and IL-1Ra is important in preventing disease in various organs, and excess production of IL-1 has been implicated in many human diseases. The IL-18 family also contains a specific inhibitor, the IL-18-binding protein (IL-18BP), which binds IL-18 in the fluid phase. The IL-18 receptor is similar to the IL-1 receptor complex, including a single ligand-binding chain and a different interacting accessory protein. IL-18 provides an important link between the innate and adaptive immune responses. Newly described IL-33 binds to the orphan IL-1 family receptor T1/ST2 and stimulates T-helper 2 responses as well as mast cells.

Intracellular signaling mechanisms regulating the activation of human eosinophils by the novel Th2 cytokine IL-33: implications for allergic inflammation

“…19,20 Indeed, how IL-33 and the two other IL-1 family cytokines IL-1b and IL-18 orchestrate and promote allergic inflammatory responses is still poorly understood. Noting the fact that IL-1b, IL-18 and IL-33 share protein sequence homology, 1 a receptor unit, and Toll-like/IL-1-receptor structure in the intracellular receptor domain, 21 we investigated the intracellular signaling pathways involved in the activation of the biological functions of human eosinophils by IL-1b, IL-18 and IL-33, paying special attention to the modulation of adhesion molecule expression, survival enhancement, and stimulation of cytokine and chemokine release. Activation of eosinophils could first be regulated at the ligand/ receptor-binding level.…”

The enigmatic processing and secretion of interleukin-33

“…1,10 However, as with the IL-1 family members IL-1b 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-1b and IL-18 are well known to be synthesized as a biologically inactive 33-kDa pro-IL-1b 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-1b and 18-kDa IL-18.…”

“…52 The pro-IL-1a is not a substrate of caspase-1 but can be cleaved by calpain to release 17-kDa IL-1a. 11,[53][54][55] As with an alarmin such as high mobility group protein-1, release of IL-1a 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-1a and high mobility group protein-1.…”

“…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-kB and mitogen-activated protein kinases, [3][4][5]11 and is involved in the polarization of T cells towards the Th2 cell phenotype 2,6,7,[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.…”

“…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-33 1-270 has been reported, variously, as the immature/mature or inactive/active IL-33.…”