Fas- and FasL-deficient mice are resistant to the induction of bleomycin-induced scleroderma.
We have recently shown that apoptosis is induced in the lesional skin in a murine scleroderma model by local bleomycin injections, and the apoptotic pathway was mainly mediated by Fas/Fas ligand (FasL) signaling. To further investigate the involvement of apoptosis in scleroderma, we examined whether the induction of dermal sclerosis is suppressed in Fas-deficient (lpr) and FasL-deficient (gld) mice. Results of histological examination showed that the induction of dermal sclerosis by bleomycin treatment was significantly suppressed in both lpr and gld mice, in comparison with wild-type mice. The ratio of collagen contents in the bleomycin-treated skin as compared with PBS-treated skin was significantly lower in both lpr and gld mice than that in wild-type mice. The number of TUNEL-positive infiltrating cells was markedly increased following bleomycin exposure (60 +/- 11.4/HPF) in comparison with PBS treatment (9.5 +/- 6.0/HPF) in wild-type mice, which was significantly decreased in both lpr (22 +/- 4.5/HPF, P < 0.05) and gld (26 +/- 6.1/HPF, P < 0.05) mice. Our findings that lpr and gld mice were resistant to the induction of dermal sclerosis by bleomycin further suggest that Fas/FasL pathway is an important contributor involved in the pathophysiology of bleomycin-induced dermal sclerosis.
Yamamoto
Toshiyuki
T
Department of Dermatology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan. toyamade@tokyo-med.ac.jp
Yokozeki
Hiroo
H
Nishioka
Kiyoshi
K
D000818:Animals; D000903:Antibiotics, Antineoplastic; D017209:Apoptosis / Q000502:physiology; D001761:Bleomycin; D003094:Collagen / Q000378:metabolism; D053222:Fas Ligand Protein / Q000235:genetics / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D007113:Immunity, Innate / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000378:metabolism / Q000473:pathology; D019014:fas Receptor / Q000235:genetics / Q000502:physiology*
D000903:Antibiotics, Antineoplastic; D053222:Fas Ligand Protein; D019014:fas Receptor; D001761:Bleomycin; D003094:Collagen