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

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-kappa B 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-1 beta, IL- 18 or IL- 33 induced phosphorylation of Erk, p38 and JNK in naive HUCBMCs, and IL- 33 or IL- 1 beta, 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 naive 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 Fc epsilon RI 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-Fc epsilon RI signals.