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Molecular Pharmacology

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Research ArticleArticle

Mitogenic Effects of Cytokines on Smooth Muscle Are Critically Dependent on Protein Kinase A and Are Unmasked by Steroids and Cyclooxygenase Inhibitors

Anna M. Misior, Huandong Yan, Rodolfo M. Pascual, Deepak A. Deshpande, Reynold A. Panettieri and Raymond B. Penn
Molecular Pharmacology February 2008, 73 (2) 566-574; DOI: https://doi.org/10.1124/mol.107.040519
Anna M. Misior
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Huandong Yan
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Rodolfo M. Pascual
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Deepak A. Deshpande
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Reynold A. Panettieri
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Raymond B. Penn
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Abstract

Excessive smooth muscle growth occurs within the context of inflammation associated with certain vascular and airway diseases. The inflammatory cytokines interleukin (IL)-1β and tumor necrosis factor-α (TNF-α) have been shown previously to inhibit mitogen-stimulated smooth muscle growth through a mechanism presumed to be dependent on the induction of cyclooxygenase-2, prostaglandins, and activation of the cAMP-dependent protein kinase (PKA). Using both molecular and pharmacological strategies, we demonstrate that the mitogenic effects of IL-1β and TNF-α on cultured human airway smooth muscle (ASM) cells are tightly regulated by PKA activity. Suppression of induced PKA activity by either corticosteroids or cyclooxygenase inhibitors converts the cytokines from inhibitors to enhancers of mitogen-stimulated ASM growth, and biological variability in the capacity to activate PKA influences the modulatory effect of cytokines. Promitogenic effects of IL-1β are associated with delayed increases in p42/p44 and phosphoinositide-3 kinase activities, suggesting a role for induced autocrine factors. These findings suggest a mechanism by which mainstream therapies such as corticosteroids or cyclooxygenase inhibitors could fail to address or exacerbate the pathogenic smooth muscle growth that occurs in obstructive airway and cardiovascular diseases.

Footnotes

  • This study was funded by National Institutes of Health grant HL58506 (to R.B.P.) and an independent investigator grant from GlaxoSmithKline (to R.B.P.).

  • A.M.M. and H.Y. contributed equally to this work.

  • ABBREVIATIONS: ASM, airway smooth muscle; Bis I, bisindolylmaleimide I; COX-2, cyclooxygenase-2; EGF, epidermal growth factor, FLU, fluticasone; GFP, green fluorescent protein; IL-1β, interleukin-1-β; mPGES1, microsomal prostaglandin E synthase-1; PGE2, prostaglandin E2; PI3K, phosphoinositide-3 kinase; PKA, cAMP-dependent protein kinase; TNF-α, tumor necrosis factor-α; VASP, vasodilator-stimulated phosphoprotein; PKI, protein kinase I; SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole.

    • Received August 1, 2007.
    • Accepted November 9, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 73 (2)
Molecular Pharmacology
Vol. 73, Issue 2
1 Feb 2008
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Research ArticleArticle

Mitogenic Effects of Cytokines on Smooth Muscle Are Critically Dependent on Protein Kinase A and Are Unmasked by Steroids and Cyclooxygenase Inhibitors

Anna M. Misior, Huandong Yan, Rodolfo M. Pascual, Deepak A. Deshpande, Reynold A. Panettieri and Raymond B. Penn
Molecular Pharmacology February 1, 2008, 73 (2) 566-574; DOI: https://doi.org/10.1124/mol.107.040519

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Research ArticleArticle

Mitogenic Effects of Cytokines on Smooth Muscle Are Critically Dependent on Protein Kinase A and Are Unmasked by Steroids and Cyclooxygenase Inhibitors

Anna M. Misior, Huandong Yan, Rodolfo M. Pascual, Deepak A. Deshpande, Reynold A. Panettieri and Raymond B. Penn
Molecular Pharmacology February 1, 2008, 73 (2) 566-574; DOI: https://doi.org/10.1124/mol.107.040519
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