IL-33 expression by mast cells is regulated by a Sphk-calcium-NFAT dependent pathway (117.5)

Abstract

Abstract IL-33 is an IL-1 family cytokine that can act extracellularly via its receptor, T1/ST2 or intracellularly. Functionally, it promotes Th2-associated immunity by enhancing several cell type activation and survival. However, the regulation of IL-33 expression is still unclear. Previously, we showed that basal expression of IL-33 in mast cells was upregulated upon IgE activation. Ca2+ mobilization was sufficient and necessary to enhance IL-33 expression in mast cells. We wanted to further investigate the pathway that drives IL-33 expression. Two major Ca2+-dependent pathways induced in mast cells are inositol trisphosphate (IP3) bound to its receptor, IP3R, and sphingosine kinase 1/2 (Sphk1/2) generated sphingosine-1-phosphate (S1P). PI3K is the upstream regulator for Sphk1. Here, we demonstrate that inhibition of PI3K and Sphk activity decreases IL-33 expression via IgE activation while ionomycin stimulation, which bypasses the inhibition, restores IL-33 expression. Interruption of NFAT and calcineurin interaction, which is downstream of Ca2+ mobilization, also decreases IL-33 expression and ionomycin can not restore it. Blocking of IP3R or NF-kB does not influence IL-33 expression but inhibits another IL-1 family cytokine, IL-1b. In summary, IL-33 is upregulated upon cross-linking of IgE receptors on mast cells and expression is dependent on Ca2+ mobilization and regulated by a PI3K-Sphk1-NFAT pathway.