Tumor necrosis factor-alpha processing inhibitor-1 inhibits skin fibrosis in a bleomycin-induced murine model of scleroderma.
Elevated serum concentration of soluble tumor necrosis factor receptor p55 (sTNFRp55) is known to correlate with the severity of systemic sclerosis (SSc). However, it has not been verified whether this increase contributes to the pathogenesis of SSc. In this study, we found that sTNFRp55 also is increased in the bleomycin (BLM)-induced murine model of SSc. Therefore, we examined the effect of tumor necrosis factor-alpha processing inhibitor-1 (TAPI-1), the inhibitor of TNFRp55 sheddase, in this model. TAPI-1 was administered weekly to mice with skin fibrosis induced by daily BLM injections. TAPI-1 significantly suppressed BLM-induced skin thickness and the number of myofibroblasts. It also inhibited the increase of serum sTNFRp55 after 3 weeks of BLM injections. The mRNA expression of collagen type I alpha1, transforming growth factor-beta1 and alpha smooth muscle actin were decreased by TAPI-1 administration. Taken together, these findings indicate that targeting the TNFalpha converting enzyme might be a new type of therapy for patients with SSc.
Terao
Mika
M
Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Murota
Hiroyuki
H
Kitaba
Shun
S
Katayama
Ichiro
I
D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D000831:Animals, Newborn; D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004151:Dipeptides / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood*; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D004151:Dipeptides; D006877:Hydroxamic Acids; C092152:N-((2-(hydroxyaminocarbonyl)methyl)-4-methylpentanoyl)-3-(2'-naphthyl)alanylalanine, 2-aminoethylamide; D047888:Receptors, Tumor Necrosis Factor, Type I; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D051722:ADAM Proteins; D000072198:ADAM17 Protein