Effects of IL-1beta, TNF-alpha, and macrophage migration inhibitory factor on prostacyclin synthesis in rat pulmonary artery smooth muscle cells.
OBJECTIVE
Cytokines have been implicated in the pathophysiology of pulmonary hypertension. We sought to explore the possibility that prostacyclin is a link.


METHODS
We tested the effects of the cytokines interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha), and macrophage migration inhibitory factor (MIF) on arachidonic acid metabolism of pulmonary artery smooth muscle cells (PASMCs) with special regard to prostacyclin (PGI2) that protects against pulmonary hypertension. Cultured rat PASMCs were treated with IL-1beta, TNF-alpha, or MIF. Expression of prostacyclin synthase (PGIS) and cyclooxygenase-2 (COX-2) mRNAs, and PGI2 synthesis, were measured.


RESULTS
We found that PGIS mRNA expression was suppressed by high concentrations of TNF-alpha and MIF, while COX-2 mRNA was induced by all three cytokines tested. IL-1beta increased PGI2 production in a dose-dependent manner. TNF-alpha and MIF also increased PGI2 production, but to a far lesser degree at high concentrations. TNF-alpha paradoxically decreased PGI2 production at a low concentration.


CONCLUSIONS
These results suggest that TNF-alpha and MIF are potentially antagonistic to the action of PGI2 in rat PASMCs via down-regulation of PGIS mRNA. Simultaneous induction of COX-2 mRNA may further counteract the action of PGI2 by increasing the levels of eicosanoids other than PGI2.
Itoh
Akihide
A
Hokkaido University School of Medicine, First Department of Medicine, Sapporo, Japan. akihide-ito@hokkaido.med.or.jp
Nishihira
Jun
J
Makita
Hironi
H
Miyamoto
Kenji
K
Yamaguchi
Etsuro
E
Nishimura
Masaharu
M
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis* / Q000276:immunology; D007375:Interleukin-1 / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000276:immunology* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000276:immunology* / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D007375:Interleukin-1; D007527:Isoenzymes; D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D015121:6-Ketoprostaglandin F1 alpha; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase