Inhibition of skin sclerosis by 15deoxy delta12,14-prostaglandin J2 and retrovirally transfected prostaglandin D synthase in a mouse model of bleomycin-induced scleroderma.
Hematopoietic prostaglandin D synthase (PGDS) is a key enzyme involved in production of the PGD and J series, which have various role in inflammation and immunity. We evaluated the effect of treatment with 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) or the injection of prostaglandin D(2) synthase (PGDS) cDNA expressing-retrovirally transfected fibroblasts on bleomycin (BLM)-induced scleroderma-like skin sclerosis. Daily injection of BLM (30 microg) for 4 weeks induced histological evidence of dermal sclerosis in C3H mice. We examined the effect of injection of 15d-PGJ(2) (30 ng twice a day) or PGDS expressing-retrovirally transfected fibroblast on BLM-induced dermal sclerosis. Administration of 15d-PGJ(2) (a nonenzymatic metabolite of PGD(2)) injection of PGDS cDNA-expressing fibroblasts significantly reduced dermal sclerosis, the hydroxyproline content, and dermal thickness. Moreover, 15-d PGJ2 down-regulation of the expression of transforming growth factor beta(1) and connective tissue growth factor which had been induced by BLM. Mast cells were also increased in the skin by BLM injection and there was prominent degranulation of these mast cells along with elevated plasma histamine levels. 15-d PGJ(2) and PGDS-expressing cells also suppressed degranulation of cultured mast cells and histamine release by these cells. These results show that 15-d PGJ(2) and PGDS-expressing cells can prevent experimental skin sclerosis induced by BLM and raise the possibility of therapeutic approaches targeting of PPARgamma for the skin lesion of scleroderma.
Kohno
Shizuka
S
Division of Rheumatology, Department of Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
Endo
Hirahito
H
Hashimoto
Atsushi
A
Hayashi
Izumi
I
Murakami
Yusuke
Y
Kitasato
Hidero
H
Kojima
Fumiaki
F
Kawai
Shinichi
S
Kondo
Hirobumi
H
D000818:Animals; D001761:Bleomycin; D055513:Connective Tissue Growth Factor; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000637:transplantation; D006636:Histamine Release; D006909:Hydroxyproline / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics; D054834:Lipocalins; D008407:Mast Cells / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D012598:Sclerosis; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014162:Transfection
C097240:15-deoxy-delta(12,14)-prostaglandin J2; C526318:CCN2 protein, mouse; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D054834:Lipocalins; D012333:RNA, Messenger; D001761:Bleomycin; D055513:Connective Tissue Growth Factor; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D006909:Hydroxyproline; D015230:Prostaglandin D2