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(Circulation Research. 2006;98:499.)
© 2006 American Heart Association, Inc.

Molecular Medicine

A Novel Prostaglandin E Receptor 4–Associated Protein Participates in Antiinflammatory Signaling

Kiyoshi Takayama, Galina K. Sukhova, Michael T. Chin, Peter Libby

From the Leducq Center for Cardiovascular Research (K.T., G.K.S., P.L.); and Cardiovascular Division (M.T.C.), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass. Current address for K.T.: Medicinal Research Center, Taisho Pharmaceutical Company, Ltd, Saitama, Japan.

Correspondence to Peter Libby, MD, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB 7, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu

Prostaglandin E₂ exerts an antiinflammatory action by ligation of the heptahelical receptor EP4 in human macrophages. Because the mechanism by which EP4 receptor stimulation suppresses inflammatory activation in macrophages remains undefined, we sought interactors with the carboxyl-terminal cytoplasmic domain of the EP4 receptor. Yeast 2-hybrid screening of the human bone marrow cDNA library with the EP4 receptor as a bait identified a cDNA clone encoding a 669-amino acid protein, designated here as EP4 receptor-associated protein (EPRAP), which contains 8 ankyrin motifs that might recruit other signaling molecules. EPRAP bound to the full-length EP4 receptor in HEK293 cells cotransfected with V5-tagged EPRAP and FLAG-tagged EP4 receptor cDNA, as anti-FLAG antibody coimmunoprecipitated EPRAP with the EP4 receptor from the lysates of cotransfected cells. Human macrophages derived from peripheral blood monocytes expressed an approximately 70-kDa protein detected by Western blotting with a polyclonal anti-EPRAP antibody. Fluorescence immunohistochemistry colocalized EPRAP with the EP4 receptor in human atheromata. Interference with EPRAP function by small interference RNA limited prostaglandin E₂–mediated suppression of chemokine expression in macrophages activated with lipopolysaccharide and tumor necrosis factor . In conclusion, the antiinflammatory action of prostaglandin E₂ in macrophages involves EPRAP that associates directly with the cytoplasmic tail of EP4 receptor.

Key Words: macrophage • arteriosclerosis • two-hybrid system techniques • prostaglandin receptor • ankyrin repeat

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