Treatment with rapamycin prevents fibrosis in tight-skin and bleomycin-induced mouse models of systemic sclerosis.
OBJECTIVE
Rapamycin, a novel macrolide immunosuppressive drug, is increasingly used as an agent for posttransplant immunosuppression and treatment of autoimmune disease. The molecular mechanism related to rapamycin-mediated immunosuppression is that rapamycin binds to FK-506 binding protein 12, and the formed complex inhibits the function of the mammalian target of rapamycin (mTOR), which in turn reduces protein phosphorylation, cell cycle progression, and cytokine production. The aim of this study was to examine the effect of rapamycin against the development of fibrosis and autoimmunity in 2 different types of systemic sclerosis (SSc) model mice.


METHODS
Tight skin (TSK/+) mice and bleomycin- induced SSc model mice were used to evaluate the effect of rapamycin on fibrosis and immunologic abnormalities. Furthermore, the antifibrotic effect of rapamycin was assessed using TSK/+ mouse fibroblasts.


RESULTS
Treatment with rapamycin reduced skin fibrosis of TSK/+ mice and skin and lung fibrosis of bleomycin-induced SSc model mice. The production of fibrogenic cytokines, such as interleukin-4 (IL-4), IL-6, IL-17, and transforming growth factor beta1, was attenuated by rapamycin. Hypergammaglobulinemia and anti-topoisomerase I antibody production were also reduced by rapamycin treatment in TSK/+ mice. In addition, mTOR expression levels were increased in TSK/+ mouse fibroblasts compared with those in wild-type mouse fibroblasts. Rapamycin treatment inhibited proliferation and collagen production of TSK/+ mouse fibroblasts in a dose-dependent manner.


CONCLUSIONS
This study is the first to show that rapamycin has a significant inhibitory effect on fibrosis in both TSK/+ and bleomycin-induced SSc model mice. These results suggest that rapamycin might be an attractive candidate for clinical trials in SSc patients.
Yoshizaki
Ayumi
A
Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Yanaba
Koichi
K
Yoshizaki
Asako
A
Iwata
Yohei
Y
Komura
Kazuhiro
K
Ogawa
Fumihide
F
Takenaka
Motoi
M
Shimizu
Kazuhiro
K
Asano
Yoshihide
Y
Hasegawa
Minoru
M
Fujimoto
Manabu
M
Sato
Shinichi
S
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020123:Sirolimus / Q000627:therapeutic use*; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018709:Statistics, Nonparametric; D058570:TOR Serine-Threonine Kinases
D016207:Cytokines; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus