Enhanced activation of cyclooxygenase-2 downregulates Th1 signaling pathway in Helicobacter pylori-infected human gastric mucosa.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Pellicanò
Antonia
A
Dipartimento di Medicina Sperimentale e Clinica, Università di Catanzaro Magna Graecia, Catanzaro, Italy.
Imeneo
Maria
M
Leone
Isabella
I
Larussa
Tiziana
T
Luzza
Francesco
F
D051546:Cyclooxygenase 2 / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation; D004789:Enzyme Activation; D005753:Gastric Mucosa / Q000276:immunology*; D016481:Helicobacter Infections / Q000201:enzymology / Q000276:immunology*; D016480:Helicobacter pylori / Q000276:immunology; D006801:Humans; D018928:Immunity, Mucosal / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*
D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human