Monocyte chemotactic protein-1 regulates leukocyte recruitment during gastric ulcer recurrence induced by tumor necrosis factor-alpha.
TNF-alpha 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)-1alpha] and C-X-C chemokines [MIP-2 and cytokine-induced neutrophil chemoattractant (CINC)-2alpha] mediate chemotaxis of monocytes and neutrophils, respectively. We examined the roles of TNF-alpha and dynamics of chemokine expression in gastric ulceration including ulcer recurrence and indomethacin-induced injury. Rats with healed chronic gastric ulcers received intraperitoneal TNF-alpha to induce ulcer recurrence. Some rats were given neutralizing antibodies against neutrophils or MCP-1 together with TNF-alpha. In a separate experiment, rats were orally administered 20 mg/kg indomethacin with or without pretreatment with pentoxifylline (an inhibitor of TNF-alpha synthesis) or anti-MCP-1 antibody. TNF-alpha (1 microg/kg) induced gastric ulcer recurrence after 48 h, which was completely prevented by anti-neutrophil antibody. TNF-alpha 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-2alpha 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-alpha/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-2alpha). Anti-MCP-1 antibody also inhibited the injury and these inflammatory responses but did not affect TNF-alpha mRNA expression. In conclusion, increased MCP-1 triggered by TNF-alpha may play a key role in gastric ulceration by regulating leukocyte recruitment and chemokine expression.
Watanabe
Toshio
T
Dept. of Gastroenterology, Osaka City Univ. Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan. watanabet@med.osaka-cu.ac.jp
Higuchi
Kazuhide
K
Hamaguchi
Masaki
M
Shiba
Masatsugu
M
Tominaga
Kazunari
K
Fujiwara
Yasuhiro
Y
Matsumoto
Takayuki
T
Arakawa
Tetsuo
T
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D000906:Antibodies; D000970:Antineoplastic Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D018932:Chemokine CCL2 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D018925:Chemokines / Q000235:genetics; D019743:Chemokines, CXC / Q000235:genetics; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000276:immunology / Q000503:physiopathology; D007213:Indomethacin / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007962:Leukocytes / Q000276:immunology*; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000494:pharmacology; D008297:Male; D009853:Omeprazole / Q000031:analogs & derivatives; D012333:RNA, Messenger / Q000032:analysis; D064750:Rabeprazole; D051381:Rats; D017208:Rats, Wistar; D012008:Recurrence; D013047:Specific Pathogen-Free Organisms; D013276:Stomach Ulcer / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D000906:Antibodies; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; C404915:Cxcl2 protein, mouse; C513296:Cxcl2 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D064750:Rabeprazole; D009853:Omeprazole; D007213:Indomethacin