Differential effects between marimastat, a TNF-alpha converting enzyme inhibitor, and anti-TNF-alpha antibody on murine models for sepsis and arthritis.
We investigated the effects of marimastat, an inhibitor of TNF-alpha converting enzyme and matrix metalloproteinases, and anti-TNF-alpha antibodies on a murine model for sepsis, and on arthritis in human TNF-alpha transgenic mice. Marimastat (25-200 mg/kg) inhibited lipopolysaccharide (LPS)-induced soluble TNF-alpha production in mice in a dose-dependent manner. At an oral dose of 200 mg/kg, marimastat almost completely inhibited LPS-induced soluble TNF-alpha production, but only slightly delayed LPS lethality. On the other hand, anti-TNF-alpha antibodies completely abolished LPS-induced morbidity. In addition, anti-TNF-alpha antibodies, but not marimastat (200 mg/kg/day), inhibited the development of arthritis in human TNF-alpha transgenic mice. These results suggest that cell surface TNF-alpha may be important in the pathogenesis of murine models for sepsis and arthritis.
Tsuji
Fumio
F
Developmental Research Division, Santen Pharmaceutical Co., Ltd., 3-9-19 Shimoshinjo, Higashiyodogawa-ku, Osaka 533-8651, Japan. ftsuji@minuet.plala.or.jp
Oki
Kenji
K
Okahara
Akihiko
A
Suhara
Hiroshi
H
Yamanouchi
Takashi
T
Sasano
Minoru
M
Mita
Shiro
S
Horiuchi
Masato
M
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000633:toxicity; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D018805:Sepsis / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
D000906:Antibodies; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C100342:marimastat; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein