Published online before print December 11, 2003, doi: 10.1161/01.RES.0000111801.48626.F4
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Submitted on April 25, 2003
Revised on November 18, 2003
Accepted on November 26, 2003
Interleukin-1
, Transforming Growth Factor-1, and Bradykinin Attenuate Cyclic AMP Production by Human Pulmonary Artery Smooth Muscle Cells in Response to Prostacyclin Analogues and Prostaglandin E2 by Cyclooxygenase-2 Induction and Downregulation of Adenylyl Cyclase Isoforms 1, 2, and 4
H. El-Haroun ;
From the Division of Respiratory Medicine, University of Nottingham, City Hospital, Nottingham, UK.
* To whom correspondence should be addressed. E-mail: alan.knox{at}nottingham.ac.uk.
Increased levels of inflammatory cytokines contribute to the pathophysiology of pulmonary hypertension. Prostacyclin (PGI2) analogues, which relax pulmonary vessels mainly through cAMP elevation, have a major therapeutic role. In this study, we show that prolonged incubation with bradykinin (BK), interleukin-1
(IL-1), and transforming growth factor-1 (TGF-1) markedly impairs cAMP accumulation in human pulmonary artery smooth muscle cells in response to short-term incubation with prostaglandin E2 (PGE2) and the PGI2 analogues iloprost and carbaprostacyclin. A similar reduction in cAMP accumulation in response to a direct adenylyl cyclase activator, forskolin, suggested that the effect was attributable to downregulation of adenylyl cyclase. Reverse transcriptase-polymerase chain reaction studies showed downregulation of adenylyl cyclase isoforms 1, 2, and 4. The effect of IL-1, BK, and TGF-1 on cAMP levels was abrogated by the selective COX-2 inhibitor NS398. Furthermore, it was mimicked by prolonged incubation with the COX-2 product PGE2 and PGI2 analogues or the COX substrate arachidonic acid, suggesting that it was mediated by endogenous prostanoids produced by COX-2. Consistent with this, IL-1, BK, and TGF-1 all induced COX-2 and PGE2 release. These results show that BK, IL-1, and TGF-1 downregulate adenylyl cyclase in human pulmonary artery smooth muscle cells via COX-2 induction and prostanoid release. This suggests a novel mechanism whereby mediators and cytokines produced in pulmonary hypertension may impair the therapeutic effects of prostacyclin analogues such as iloprost and carbaprostacyclin.
Key words: interleukin-1
•
transforming growth factor-1 •
bradykinin •
cAMP •
adenylyl cyclase
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