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Prostaglandin E₂ Inhibits Specific Lung Fibroblast Functions via Selective Actions of PKA and Epac-1

¹ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Marc Peters-Golden, M.D., Division of Pulmonary and Critical Care Medicine, 1150 W. Medical Center Drive, 6301 MSRB III, Ann Arbor, MI 48109-5642. E-mail: petersm{at}umich.edu

Via their capacities for proliferation and synthesis of matrix proteins such as collagen, fibroblasts are key effectors in the pathogenesis of fibrotic disorders such as idiopathic pulmonary fibrosis. Prostaglandin E₂ (PGE₂) potently inhibits these functions in lung fibroblasts through receptor ligation and production of the second messenger cAMP, but the downstream pathways mediating such actions have not been fully characterized. We sought to investigate the roles of the cAMP effectors protein kinase A (PKA) and exchange protein activated by cAMP-1 (Epac-1) in modulating these two functions in primary human fetal lung IMR-90 fibroblasts. The specific roles of these two effector pathways were examined by treating cells with PKA-specific (6-bnz-cAMP) and Epac-specific (8-pCPT-2'-O-Me-cAMP) agonists, inhibiting PKA with the inhibitor KT 5720, overexpressing the PKA catalytic subunit, and silencing Epac-1 using short hairpin RNA. PGE₂ inhibition of collagen I expression was mediated exclusively by activation of PKA, while inhibition of fibroblast proliferation was mediated exclusively by activation of Epac-1. PGE₂ and Epac-1 inhibited cell proliferation through activation of the small GTPase Rap1, since decreasing Rap1 activity by transfection with Rap1GAP or the dominant-negative Rap1N17 prevented, and transfection with the constitutively active Rap1V12 mimicked, the anti-proliferative effects of PGE₂. On the other hand, PKA inhibition of collagen was dependent on inhibition of protein kinase C-. The selective use of PKA and Epac-1 pathways to inhibit distinct aspects of fibroblast activation illustrate the pleiotropic ability of PGE₂ to inhibit diverse fibroblast functions.

Key Words: proliferation • collagen • cAMP • pulmonary fibrosis

CLINICAL RELEVANCE Our findings show that via divergent signaling pathways, prostaglandin E2 is able to inhibit distinct fibroblast functions. Understanding these pathways may provide novel therapeutic targets that can be used to limit fibroproliferation.

 

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