Cis3/Socs3/Ssi3 Plays a Negative Regulatory Role in Stat3 Activation and Intestinal Inflammation

Abstract

Immune and inflammatory systems are controlled by multiple cytokines, including interleukins (ILs) and interferons. These cytokines exert their biological functions through Janus tyrosine kinases and signal transducer and activator of transcription (STAT) transcription factors. We recently identified two intrinsic Janus kinase (JAK) inhibitors, JAK binding protein (JAB; also referred to as suppressor of cytokine signaling [SOCS1]/STAT-induced STAT inhibitor [SSI1]) and cytokine-inducible SH2 protein (CIS)3 (or SOCS3/SSI3), which play an essential role in the negative regulation of cytokine signaling. We have investigated the role of STATs and these JAK inhibitors in intestinal inflammation. Among STAT family members, STAT3 was most strongly tyrosine phosphorylated in human ulcerative colitis and Crohn's disease patients as well as in dextran sulfate sodium (DSS)-induced colitis in mice. Development of colitis as well as STAT3 activation was significantly reduced in IL-6–deficient mice treated with DSS, suggesting that STAT3 plays an important role in the perpetuation of colitis. CIS3, but not JAB, was highly expressed in the colon of DSS-treated mice as well as several T cell–dependent colitis models. To define the physiological role of CIS3 induction in colitis, we developed a JAB mutant (F59D-JAB) that overcame the inhibitory effect of both JAB and CIS3 and created transgenic mice. DSS induced stronger STAT3 activation and more severe colitis in F59D-JAB transgenic mice than in their wild-type littermates. These data suggest that hyperactivation of STAT3 results in severe colitis and that CIS3 plays a negative regulatory role in intestinal inflammation by downregulating STAT3 activity.

Signal Transducer and Activator of Transcription 3 - A Promising Target in Colitis-Associated Cancer

“…The combination of soluble IL-6 receptor (sIL-6R) and IL-6 stimulates cells that only express gp130 and not IL-6R, a process known as trans-signaling. IL-6 signaling through STAT3 has been extensively studied (Suzuki et al, 2001;Mudter and Neurath, 2007;Tian et al, 2011). This system plays a central role in several immunologic reactions during the development of IBD, and circulating levels of IL-6 and sIL-6R correlate with many clinical features of CD and UC (Mitsuyama et al, 1995;Van Kemseke et al, 2000;Scheller et al, 2006;Rose-John et al, 2009).…”

STAT3 in immune responses and inflammatory bowel diseases

“…It is interesting to note that STAT3 was also found to be highly tyrosine phosphorylated in epithelial and lamina propria cells of human ulcerative colitis and Crohn's disease patients as well as in dextran sulfate sodium (DSS)-induced colitis in mice [55], possibly indicating a potential role of STAT3 in epithelial cells during colitis generation.…”

Role of STAT3 in inflammatory bowel disease

“…Indeed, several recent studies have focused on the role of STATs on IBD. Among STATs, the role of STAT3 in IBD has been most well documented by recent studies obtained from human IBD studies [6][7][8] and experimental IBD models [9][10][11][12] . These studies have revealed that STAT3 is in a unique position for pathogenesis of IBD, because STAT3 plays distinct roles between innate immune cells and acquired immune cells.…”