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Activation of Phosphatase and Tensin Homolog on Chromosome 10 Mediates the Inhibition of FcR Phagocytosis by Prostaglandin E₂ in Alveolar Macrophages¹

Claudio Canetti^2,*,, Carlos H. Serezani^2,*, Rachelle G. Atrasz^*, Eric S. White^*, David M. Aronoff and Marc Peters-Golden^3,*

^* Division of Pulmonary and Critical Care Medicine and Division of Infectious Diseases, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109; and Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

PGE₂ has important inhibitory effects on the macrophage host defense functions of phagocytosis and killing, yet the molecular mechanisms involved remain to be fully elucidated. PGE₂ causes an elevation of cAMP in alveolar macrophages (AMs), which in turn activates the cAMP effector targets, protein kinase A and the exchange protein activated by cAMP (Epac)-1. We now report that FcR-induced PI3K/Akt and ERK-1/2 activation are inhibited by PGE₂ in AMs. By specifically inhibiting the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in AMs, we attenuated the inhibitory effects of both PGE₂ and a specific Epac-1 agonist (8-pCPT-2'-O-Me-cAMP) on FcR-mediated phagocytosis and Akt/ERK-1/2 activation; PTEN inhibition also decreased PGE₂-induced suppression of bacterial killing by AMs. Moreover, PGE₂ and the Epac-1 agonist induced an increase in PTEN lipid phosphatase activity, and this was associated with decreased tyrosine phosphorylation on PTEN—a mechanism known to regulate PTEN activity. Using a pharmacological approach, we demonstrated a role for Src homology 2-containing protein tyrosine phosphatase-1 in the PGE₂-induced tyrosine dephosphorylation of PTEN. Collectively, these data reveal that PGE₂, via Epac-1 activation, enhances SHP-1 activity, resulting in increased PTEN activity. We suggest that this mechanism contributes to the ability of PGE₂ to inhibit PI3K-dependent innate immune signaling in primary macrophages.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants HL078727 (to D.M.A.) and HL058897 (to M.P.-G.), American Lung Association Research Grant RG8909N (to D.M.A.), Conselho Nacional de Desenvolvimento Científico e Tecnológico (to C.C.), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (to C.C.).

² C.C. and C.H.S. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Marc Peters-Golden, University of Michigan Health System, 6301 Medical Science Research Building III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5642. E-mail address: petersm{at}umich.edu

⁴ Abbreviations used in this paper: PIP3, phosphatidylinositol 3,4,5-triphosphate; PTEN, phosphatase and tensin homolog deleted on chromosome 10; AM, alveolar macrophage; Epac-1, exchange protein activated by cAMP-1; PKA, protein kinase A; SHP-1, Src homology 2-containing protein tyrosine phosphatase-1; SHPI, -bromo-4-(carboxymethoxy)-acetophenone.

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