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-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. INTRODUCTIONIn 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) cells 6,7 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-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, 15-20 bosophils, 14,20-24 eosinophils, 24-26 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, rheum...

Targeting IL-33 in Autoimmunity and Inflammation

“…In contrast, caspase-1 cleaves pro-IL-33 into an inactive form (Cayrol and Girard, 2009). Moreover, unlike pro-IL-1a, the proform of IL-33 is biologically active and also contains nuclear localization sequences (like pro-IL-1a) allowing it to act both as an intracellular nuclear factor and as an extracellular cytokine (Zhao and Hu, 2010). Proteases such as calpain, cathepsin G, and elastase can cleave pro-IL-33 into more potent mature forms Garlanda et al, 2013) (Fig.…”

Participation of MyD88 and Interleukin-33 as Innate Drivers of Th2 Immunity to Trichinella spiralis

“…The receptor for IL-33 is ST2, a member of the IL-1 family of cytokine receptors (20,38). Unlike other IL-1 family cytokines, IL-33 is released in its active form by necrotic cells (36,39,40). Normally found in epithelial and endothelial cells, adipocytes, astrocytes, and airway smooth muscle cells, IL-33 may also be detected in mast cells, dendritic cells, and monocytes under inflammatory conditions (41)(42)(43)(44)(45)(46)(47).…”

The Dual Function Cytokine IL-33 Interacts with the Transcription Factor NF-κB To Dampen NF-κB–Stimulated Gene Transcription

“…Like IL-1a, IL-1b, and IL-18, IL-33 does not contain a leader sequence, and how it is released from cells is at present unclear (reviewed in Ref. 18). In fact, only few reports actually show IL-33 release after stimulation (19)(20)(21), although increased levels of IL-33 protein in tissues and in circulation have been reported in several diseases (reviewed in Ref.…”