Over-expression of Ste20-related proline/alanine rich kinase (SPAK) exacerbates experimental colitis in mice

摘要

Inflammatory bowel disease (IBD), mainly Crohn’s disease (CD) and ulcerative colitis (UC), are characterized by epithelial barrier disruption and altered immune regulation. Colonic Ste20-like proline/alanine-rich kinase (SPAK) plays a role in intestinal inflammation, but its underlying mechanisms need to be defined. Both SPAK-transfected Caco2-BBE cells and villin-SPAK transgenic (TG) FVB/6 mice exhibited loss of intestinal barrier function. Further studies demonstrated that SPAK significantly increased paracellular intestinal permeability to fluorescein isothiocyanate (FITC)-dextran. In vivo studies using the mouse models of colitis induced by dextran sulfate sodium (DSS) and trinitrobenzene sulfonic acid (TNBS) showed that TG FVB/6 mice were more susceptible to DSS and TNBS treatment than wild-type FVB/6 mice, as demonstrated by clinical and histological characteristics and enzymatic activities. Consistent with this notion, we found that SPAK increased intestinal epithelial permeability, which likely facilitated the production of inflammatory cytokines in vitro and in vivo and aggravated bacterial translocation in TG mice under DSS treatment, consequently established a context favorable for the triggering of intestinal inflammation cascades. In conclusion, over-expression of SPAK inhibits maintenance of intestinal mucosal innate immune homeostasis, which makes regulation of SPAK important to attenuate pathological responses in IBD.