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Am J Physiol Lung Cell Mol Physiol 294: L553-L562, 2008. First published December 21, 2007; doi:10.1152/ajplung.00044.2006
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IL-1β, BK, and TGF-β1 attenuate PGI2-mediated cAMP formation in human pulmonary artery smooth muscle cells by multiple mechanisms involving p38 MAP kinase and PKA

H. El-Haroun, D. L. Clarke, K. Deacon, D. Bradbury, A. Clayton, A. Sutcliffe, and Alan J. Knox

Division of Respiratory Medicine, University of Nottingham, City Hospital, Nottingham, United Kingdom

Submitted 3 February 2006 ; accepted in final form 17 December 2007

We have previously shown that interleukin (IL)-1β, transforming growth factor (TGF)-β1, or bradykinin (BK) impair cAMP generation in response to prostacyclin analogs in human pulmonary artery smooth muscle (PASM), suggesting that inflammation can impair the effects of prostacyclin analogs on PASM in pulmonary hypertension. Here we explored the biochemical mechanisms involved. We found that IL-1β, BK, and TGF-β1 reduced adenylyl cyclase isoform 1, 2, and 4 mRNA, increased G{alpha}i protein levels, and reduced prostacyclin receptor (IP receptor) mRNA expression. In contrast, G{alpha}s protein levels were unchanged. Protein kinase A (PKA) (H-89, KT-2750, PKIm) and p38 mitogen-activated protein (MAP) kinase (SB-202190) inhibitors attenuated these effects, but protein kinase C (bisindolylmaleide) or phosphoinositol 3-kinase (LY-294002) inhibitors did not. Fluorescent kemptide assay and Western blotting confirmed that PKA and p38 MAP kinase were activated by IL-1β, BK, and TGF-β1. These studies suggest that IL-1β, BK, and TGF-β1 impair IP receptor-mediated cAMP accumulation by multiple effects on different components of the signaling pathway and that these effects are PKA and p38 MAP kinase dependent.

pulmonary artery smooth muscle; kinases; adenosine 3',5'-cyclic monophosphate; prostacyclin receptor


Address for reprint requests and other correspondence: A. J. Knox, Division of Respiratory Medicine, Univ. of Nottingham, Clinical Science Bldg., City Hospital, Nottingham, NG5 1PB, United Kingdom (e-mail: alan.knox{at}nottingham.ac.uk.)






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