IL-33 can promote survival, adhesion and cytokine production in human mast cells

Abstract

IL-33 is a recently identified member of the IL-1 family of molecules, which also includes IL-1 and IL-18. IL-33 binds to the receptor, T1/ST2/IL-1R4, and can promote cytokine secretion by Th2 cells and NF-kB phosphorylation in mouse mast cells. However, the effects of these molecules, especially IL-33, in human mast cells are poorly understood. Expression of the receptors for IL-1 family molecules, specifically, IL-1R1, IL-18R and T1/ST2, was detectable intracellularly in human umbilical cord blood-derived mast cells (HUCBMCs) by flow cytometry, but was scarcely detectable on the cells' surface. However, IL-1b, IL-18 or IL-33 induced phosphorylation of Erk, p38 and JNK in naïve HUCBMCs, and IL-33 or IL-1b, but not IL-18, enhanced the survival of naive HUCBMCs and promoted their adhesion to fibronectin. IL-33 or IL-1b also induced IL-8 and IL-13 production in naïve HUCBMCs, and enhanced production of these cytokines in IgE/anti-IgE-stimulated HUCBMCs, without enhancing secretion of either PGD 2 or histamine. Moreover, IL-33-mediated IL-8 production by HUCBMCs was markedly reduced by the p38 MAPK inhibitor, SB203580. In contrast to findings with mouse mast cells, IL-18 neither induced nor enhanced secretion of the mediators PGD 2 or histamine by HUCBMCs. Our findings identify previously unknown functions of IL-33 in human mast cells. One of these is that IL-33, like IL-1b, can induce cytokine production in human mast cells even in the absence of stimuli of FceRI aggregation. Our findings thus support the hypothesis that IL-33 may enhance mast cell function in allergic disorders and other settings, either in the presence or absence of co-stimulation of mast cells via IgE/antigen-FceRI signals.

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

“…5 In addition, IL-33 has been shown to promote the maturation and survival of human mast cells and to induce their secretion of cytokines IL-5 and IL-13, which promote the survival and effector functions of eosinophils. 6,7 Together with the results from mouse models, 1,3,4 these results indicate that IL-33 might play a pivotal role in the exacerbation of allergic inflammation in allergic diseases mediated by the activation of eosinophils.…”

The Immune-Modulating Cytokine and Endogenous Alarmin Interleukin-33 Is Upregulated in Skin Exposed to Inflammatory UVB Radiation

“…41 Our study revealed that UV-induced progressor SCC express significantly higher constitutive IL-33 levels than regressor SCC. IL-33 has been shown to prevent apoptosis in cardiomyocytes 60 and to promote the survival and viability of mast cells 61 as well as eosinophils. 62 More recently, IL-33 was shown to induce extracellular signal-regulated kinase (ERK) expression in lung epithelial cells.…”

Interleukin-33 drives hepatic fibrosis through activation of hepatic stellate cells

“…37 Iikura et al 38 reported that IL-33-mediated IL-8 production by human umbilical cord bloodderived mast cells was markedly reduced by the p38-MAPK inhibitor, SB203580, which might imply that IL-33 can activate p38-MAPK. Sakai et al 39 reported that IL-33 is an important endogenous regulator of hepatic ischemia/reperfusion injury through activation of NF-κB, MAPK, cyclin D1 and Bcl-2 expression in hepatocytes, which limits liver injury and reduces the stimulus for inflammation.…”