FR167653, a p38 mitogen-activated protein kinase inhibitor, aggravates experimental colitis in mice

Abstract

AIM:To investigate the effects of FR167653 on the development of dextran sulfate sodium (DSS)-induced colitis in mice. METHODS: BALB/c mice were fed rodent chow containing 3.5% (wt/wt) DSS. The recipient mice underwent intra-peritoneal injection of vehicles or FR167653 (30 mg/kg per day). The mice were sacrificed on day 14, and the degree of colitis was assessed. Immunohistochemical analyses for CD4 + T cell and F4/80 + macrophage infiltration were also performed. Mucosal cytokine expression was analyzed by RT-PCR. RESULTS: The body weight loss was more apparent in the FR167653-treated DSS mice than in the vehicletreated DSS mice. The colon length was shorter in the FR167653-treated DSS mice than in the vehicle-treated DSS mice. Disease activity index and histological colitis score were significantly higher in FR167653-than in vehicle-treated DSS animals. Microscopically, mucosal edema, cellular infiltration (CD4 T cells and F4/80 macrophages), and the disruption of the epithelium were much more severe in FR167653-treated mice than in controls. Mucosal mRNA expression for interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were found to be markedly reduced in FR167653-treated DSS mice. CONCLUSION: Treatment with FR167653 aggravated DSS colitis in mice. This effect was accompanied by a reduction of mucosal IL-1β and TNF-α expression, suggesting a role of p38 mitogen-activated protein kinase (MAPK)-mediated proinflammatory cytokine induction in host defense mechanisms.

Probiotic-Derived Polyphosphate Enhances the Epithelial Barrier Function and Maintains Intestinal Homeostasis through Integrin–p38 MAPK Pathway

“…It has been reported that an intraperitoneal injection of the p38 MAPK-specific inhibitor FR167653 aggravated 3% DSS-induced colitis [35]. This suggests that activation of the p38 MAPK pathway is a protective reaction against the excess inflammation.…”

“…P38 MAPK is a class of mitogen-activated protein kinases responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and is involved in cell differentiation and apoptosis. It has been reported that an intraperitoneal injection of the p38 MAPK-specific inhibitor FR167653 aggravated 3% DSS-induced colitis [35] . This suggests that activation of the p38 MAPK pathway is a protective reaction against the excess inflammation.…”

Interleukin-10 Enhances the Intestinal Epithelial Barrier in the Presence of Corticosteroids through p38 MAPK Activity in Caco-2 Monolayers: A Possible Mechanism for Steroid Responsiveness in Ulcerative Colitis

“…Hollenbach et al . found that inhibition of p38 MAPK was able to drastically reduce colonic NF-kB activity with a consequent improvement of intestinal lesions in a murine model [ 27 ], whereas in other studies inhibition of p38 MAPK activation worsened the course of 2,4,6-trinitrobenzenesulfonic (TNBS) acid or dextran sulphate sodium (DSS) induced colitis [ 28 , 29 ].…”

Wound Healing Responses at the Gastrointestinal Epithelium: a Close Look at Novel Regulatory Factors and Investigative Approaches

“…Additionally, epidermal growth factor receptor (EGFR)-induced intestinal epithelial cell migration depends on MAPKp38 signaling mediated by the family of Src kinases [29,30]. Intestinal ischemia/reperfusion injury leads to rapid activation of MAPKp38 signaling in intestinal epithelial cells [31,32], and inhibition of MAPKp38 signaling exacerbates DSS-induced colitis, as well as TNBS-induced weight-loss in mice [33,34]. Activation of MAPKp38 signaling by TGF-β is crucial in inducing epithelial to mesenchymal transformation, one of the deciding steps in early epithelial restitution [35,36].…”