Role of nucleotide binding oligomerization domain-like receptor protein 3 inflammasome in stress-induced gastric injury.

Abstract

The inflammasomes promote pro-caspase-1 cleavage, leading to processing of pro-interleukin (IL)-1β into its mature form. We investigated the role of the IL-1β and nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in gastric injury in mice receiving water-immersion restraint stress (WIRS), focusing on the cyclooxygenase (COX)-2/prostaglandin (PG) E2 axis. To induce gastric injury, the mice were placed in a restraint cage and immersed in the water bath to the level of the xiphoid process. Protein levels of mature caspase-1 and IL-1β were assessed by western blotting. Water-immersion restraint stress induced gastric injury with increase in IL-1β expression by activation of NLRP3 inflammasome. Exogenous IL-1β attenuated the injury, whereas anti-IL-1β neutralizing antibody and IL-1β receptor antibody aggravated it. NLRP3-/- and caspase-1-/- mice enhanced the injury with reducing of mature IL-1β, and this aggravation was reduced by exogenous IL-1β supplementation. Toll-like receptor 4-/- mice were hyporesponsive to WIRS in terms of mature IL-1β production. Rabeprazole attenuated the injury with preventing inflammasome activation. WIRS injured the stomach with promotion of COX-2 mRNA and PGE2 production, and exogenous IL-1β enhanced these molecules, while IL-1β immunoneutralization exerted opposite effect. PGE2 supplementation abolished the hypersensitivity in NLRP3-/- and caspase-1-/- mice through negative regulation of inflammatory cytokines. These results suggest that NLRP3 inflammasome-derived IL-1β plays a protective role in stress-induced gastric injury via activation of the COX-2/PGE2 axis. Toll-like receptor 4 signaling and gastric acid may be involved in NLRP3 inflammasome activation.