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INFLAMMATION/IMMUNITY/MEDIATORS
Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1–4-3 Asahimachi, Abeno-ku, Osaka 545–8585, Japan
Submitted 2 September 2003 ; accepted in final form 7 June 2004
TNF-
has numerous biological activities, including the induction of chemokine expression, and is involved in many gastric injuries. C-C chemokines [monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1] and C-X-C chemokines [MIP-2 and cytokine-induced neutrophil chemoattractant (CINC)-2] mediate chemotaxis of monocytes and neutrophils, respectively. We examined the roles of TNF- and dynamics of chemokine expression in gastric ulceration including ulcer recurrence and indomethacin-induced injury. Rats with healed chronic gastric ulcers received intraperitoneal TNF- to induce ulcer recurrence. Some rats were given neutralizing antibodies against neutrophils or MCP-1 together with TNF-. In a separate experiment, rats were orally administered 20 mg/kg indomethacin with or without pretreatment with pentoxifylline (an inhibitor of TNF- synthesis) or anti-MCP-1 antibody. TNF- (1 µg/kg) induced gastric ulcer recurrence after 48 h, which was completely prevented by anti-neutrophil antibody. TNF- increased the number of macrophages and MCP-1 mRNA expression in scarred mucosa from 4 h, whereas it increased MPO activities (marker of neutrophil infiltration) and mRNA expression of MIP-2 and CINC-2 from 24 h. Anti-MCP-1 antibody inhibited leukocyte infiltration with reduction of the levels of C-X-C chemokines and prevented ulcer recurrence. Indomethacin treatment increased TNF-/chemokine mRNA expression from 30 min and induced macroscopic erosions after 4 h. Pentoxifylline inhibited the indomethacin-induced gastric injury with reduction of neutrophil infiltration and expression of chemokine (MCP-1, MIP-2, and CINC-2). Anti-MCP-1 antibody also inhibited the injury and these inflammatory responses but did not affect TNF- mRNA expression. In conclusion, increased MCP-1 triggered by TNF- may play a key role in gastric ulceration by regulating leukocyte recruitment and chemokine expression.
ulceration; cytokine; macrophage; real-time reverse transcriptase-polymerase chain reaction
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