IL-4 signaling via STAT6 induces human resistin expression

Abstract

Abstract Human resistin (hRetn) has been implicated as a detrimental protein during helminth infection, where it impairs helminth expulsion. Current literature shows that LPS signaling via NFkB can promote hRetn expression. Promoter analysis of the hRetn gene revealed both NFκB and STAT6 transcription factor binding sites. This suggested that hRetn is not only regulated by TLR ligands but also by Th2 cytokines. Accordingly, we tested the ability of various TLR ligands and IL-4 to stimulate hRetn in bone marrow-derived macrophages (BMDM) from hRetn transgenic (Tg+) mice. We found that LPS and IL-4 stimulation significantly increased hRetn. Further, IL-4-induced hRetn expression was abrogated when BMDM were treated with a STAT6 inhibitor, confirming STAT6 dependent hRetn expression. We tested the effects of IL-4 in vivo by administering IL-4 complexes (IL-4c) intratracheally and intraperitoneally to hRetn Tg+ mice. We observed local and systemic IL-4-induced hRetn mRNA in blood cells, peritoneal exudate cells and the whole lung. To elucidate the relevance of these findings in humans, we stimulated human neutrophils, monocytes and peripheral blood mononuclear cells (PBMC) with IL-4 and discovered that neutrophils produced the most hRetn. Similar to mouse BMDM, the IL-4-induced hRetn in human PBMCs was blocked by STAT6 inhibitors. Collectively, these data suggest that IL-4 signaling via STAT6 induces hRetn and these results are supportive of a novel signaling pathway for hRetn. Future studies will investigate the functional relevance of STAT6 regulation of hRetn, which could provide new insights into controlling the outcome of several Th2 inflammatory diseases such as helminth infection and asthma.