Cyclooxygenase-2 expression and prostaglandin E2 biosynthesis are enhanced in scleroderma fibroblasts and inhibited by UVA irradiation.
OBJECTIVE
We and others reported on the beneficial effects of combined therapy using 8-methoxypsoralen and long wave ultraviolet light (PUVA therapy) in the treatment of scleroderma. We now investigate the mechanism by which PUVA therapy is effective by comparing interleukin 1beta (IL-1beta) mediated signal transduction in scleroderma fibroblasts and those from normal skin.


METHODS
Prostaglandin E2 (PGE2) production and expression of cytosolic phospholipase A2 (cPLA2), cyclooxygenase (COX)-1, and COX-2 (enzymes that regulate PGE2 production) were examined in untreated and IL-1beta treated fibroblasts from scleroderma involved and normal skin. The effect of UVA irradiation on enzyme expression and PGE2 production was examined. PGE2 was measured by a competitive radioimmunoassay and enzyme expression was analyzed by Western immunoblotting and Northern blotting.


RESULTS
Constitutive PGE2 production was significantly upregulated and IL-1beta induced PGE2 production was increased by the enhancing expression of both COX-2 mRNA and protein in fibroblasts from scleroderma involved skin; PGE2 production and COX-2 expression were inhibited by UVA irradiation.


CONCLUSIONS
Enhanced PGE2 production regulated by COX-2 expression in scleroderma fibroblasts may contribute to the development of this disorder. PUVA therapy might exhibit its beneficial effect, at least in part, by inhibiting COX-2 expression transcriptionally and translationally, with subsequent inhibition of PGE2 production.
Kanekura
T
T
Department of Dermatology, Faculty of Medicine, Kagoshima University, Japan. takuro1@m2.kufm.kagoshima-u.ac.jp
Higashi
Y
Y
Kanzaki
T
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D003593:Cytoplasm / Q000201:enzymology; D015232:Dinoprostone / Q000032:analysis / Q000096:biosynthesis*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D015971:Gene Expression Regulation, Enzymologic / Q000528:radiation effects; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D007527:Isoenzymes / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D008565:Membrane Proteins; D008875:Middle Aged; D010741:Phospholipases A / Q000032:analysis / Q000096:biosynthesis; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D012595:Scleroderma, Systemic / Q000378:metabolism*; D012867:Skin / Q000166:cytology / Q000378:metabolism; D014466:Ultraviolet Rays
D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054467:Phospholipases A2; D015232:Dinoprostone