Enhanced Activation of Cyclooxygenase‐2 Downregulates Th1 Signaling Pathway in Helicobacter pylori‐infected Human Gastric Mucosa

Abstract

Evidence suggests that an impaired T-cell response against Helicobacter pylori plays a role in the pathogenesis of H. pylori-related diseases. Cyclooxygenase (COX) 2 has been shown to inhibit the production of T-helper (Th) 1 cytokines. This study aimed to ascertain whether COX-2 downregulates Th1 signaling pathway in human gastric mucosa colonized by H. pylori. COX-2 expression and prostaglandin E(2) (PGE(2)) production were determined in total proteins extracted from freshly obtained gastric biopsies of H. pylori-infected and uninfected patients by Western blotting and enzyme-linked immunosorbent assay (ELISA). Phosphorylated (p)STAT4, pSTAT1, T-bet, and pSTAT6 expression and interleukin (IL)-12, interferon (IFN)-gamma, and IL-4 production were also determined by Western blotting and ELISA, respectively, in total protein extracts from gastric biopsy cultures of H. pylori-infected patients treated without and with COX-2 inhibitor NS-398. Enhanced expression of COX-2 and production of PGE(2) was found in H. pylori-infected compared to uninfected patients. COX-2 inhibition significantly increased expression of Th1 transcription factors along with production of IL-12 and IFN-gamma. By contrast, no changes in the expression of STAT6 and production of IL-4 were found. This study provides a mechanism by which H. pylori may actually interfere with normal T-cell activation in human gastric mucosa, possibly enhancing its pathogenicity. The use of COX-2 selective inhibitors as immunomodulators in the course of H. pylori infection deserves investigations.