STAT5b Controls IgE-mediated Mast Cell Functions In Vitro and In Vivo

Abstract

Abstract Signal Transducers and Activators of Transcription (STATs) are latent transcription factors that mediate a number of cellular responses including but not limited to cell survival, proliferation and differentiation. This protein family consists of seven members, STATs 1 – 6 including two closely related molecules, STAT5a and STAT5b, that show 96% amino acid sequence homology and are critical for lymphoid, myeloid, and erythroid cell development and function. We recently identified Stat5b as the critical regulator of IgE-mediated cytokine production in mast cells. STAT5b knockout (KO) cells show decreased cytokine production in vitro. In vivo STAT5b KO mice demonstrate decreased sensitivity to IgE-mediated passive systemic anaphylaxis accompanied with decreased production of IL-6 and IL-13 compared to wildtype counterparts. There was no difference in MAR-1-mediated passive systemic anaphylaxis or mast cell number and distribution. Interestingly STAT5b KO mice demonstrate elevated levels of serum IgE and an exacerbated response to histamine-mediated passive systemic anaphylaxis. We previously found that Fyn-mediated Stat5 tyrosine phosphorylation is critical for Stat5-dependent effects. The current work demonstrates that Stat5b is also phosphorylated on serine residues during IgE signaling in mast cells, via a Src-independent pathway requiring PI3-kinase function. Preliminary data show that STAT5b tyrosine and serine phosphorylation either independently or in tandem regulate IgE-induced cytokine production. Elucidating the role of STAT5b in the inflammatory response as well as the key players in STAT5b serine phosphorylation will yield new targets for mast cell-associated diseases.