title: Overexpression of Ste20-related proline/alanine-rich kinase exacerbates experimental colitis in mice.
abstract: Inflammatory bowel disease, mainly Crohn's disease and ulcerative colitis, 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 FITC-dextran. In vivo studies using the mouse models of colitis induced by dextran sulfate sodium (DSS) and trinitrobenzene sulfonic acid showed that TG FVB/6 mice were more susceptible to DSS and trinitrobenzene sulfonic acid 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, aggravated bacterial translocation in TG mice under DSS treatment, and consequently established a context favorable for the triggering of intestinal inflammation cascades. In conclusion, overexpression of SPAK inhibits maintenance of intestinal mucosal innate immune homeostasis, which makes regulation of SPAK important to attenuate pathological responses in inflammatory bowel disease.
authors.affiliation: Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. yyan2@emory.edu
authors.forename: Yutao
authors.initials: Y
authors.lastname: Yan
authors.forename: Hamed
authors.initials: H
authors.lastname: Laroui
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Ingersoll
authors.forename: Saravanan
authors.initials: S
authors.lastname: Ayyadurai
authors.forename: Moiz
authors.initials: M
authors.lastname: Charania
authors.forename: Stephen
authors.initials: S
authors.lastname: Yang
authors.forename: Guillaume
authors.initials: G
authors.lastname: Dalmasso
authors.forename: Tracy S
authors.initials: TS
authors.lastname: Obertone
authors.forename: Hang
authors.initials: H
authors.lastname: Nguyen
authors.forename: Shanthi V
authors.initials: SV
authors.lastname: Sitaraman
authors.forename: Didier
authors.initials: D
authors.lastname: Merlin
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D000818:Animals; D018938:Caco-2 Cells; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D015212:Inflammatory Bowel Diseases / Q000201:enzymology* / Q000235:genetics* / Q000276:immunology; D007413:Intestinal Mucosa / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010539:Permeability; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology
chemical_list: C486407:Stk39 protein, mouse; D017346:Protein Serine-Threonine Kinases; C486409:STK39 protein, human