Mast cells play key roles in both adaptive and innate immune responses leading to type-2 inflammation. IL-33, an epithelium-derived cytokine, is released mainly from damaged tissue as an “alarmin” after virus infection or protease antigen exposure. IL-33 release leads to activation of various cell types. IL-33 had been known to activate mast cells directly to produce IL-5 and IL-13. However, our recent studies using a protease-induced asthma model found that IL-33 also induces regulatory T-cell production by activating mast cells. We have now comprehensively examined gene-expression profiles to elucidate how IL-33 alters mast cell function.
Human mast cells were generated by 12-week culture of peripheral blood hematopoietic stem cells in the presence of SCF and IL-6. Mast cells were stimulated with IL-33 or with anti-IgE mAb after IgE-sensitization. mRNA expression was determined by microarray and qPCR. Chemotaxis assay was performed using Boyden chambers, and ERK phosphorylation was determined by western blotting.
IL-33 stimulation, but not anti-IgE mAb stimulation, induced CCR7 mRNA expression in mast cells. Upon exposure to CCL19 and CCL21 (CCR7 ligands), IL-33-stimulated mast cells showed significant chemotaxis and ERK phosphorylation in dose- and time-dependent manners, but naïve mast cells did not.
Conclusions: IL-33 induces not only IL-5 and IL-13 production by human mast cells but also expression of functional CCR7 that may facilitate mast cell–T cell interaction following CCL19/CCL21 exposure.