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Published online before print April 1, 2004

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(Journal of Leukocyte Biology. 2004;76:227-236.)
© 2004 by Society for Leukocyte Biology

Prostaglandin E₂ receptors EP2 and EP4 are up-regulated in peritoneal macrophages and joints of pristane-treated mice and modulate TNF- and IL-6 production

Jun Akaogi^*, Hidehiro Yamada, Yoshiki Kuroda^*, Dina C. Nacionales^*, Westley H. Reeves^*, and Minoru Satoh^*,,1

^* Division of Rheumatology and Clinical Immunology, Department of Medicine, and
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville; and
Department of Internal Medicine, St. Marianna University, Kawasaki, Japan

¹Correspondence: Division of Rheumatology and Clinical Immunology, University of Florida, P.O. Box 100221, Gainesville, FL 32610-0221. E-mail: satohm{at}medicine.ufl.edu

Prostaglandin E₂ (PGE₂) can have pro- or anti-inflammatory effects, depending on engagement of different PGE₂ receptor (EP) subtypes. The role of EPs in regulating autoimmune inflammation was studied in the murine arthritis/lupus model induced by pristane. Peritoneal macrophages were isolated (biomagnetic beads) from BALB/c, DBA/1, or C57BL/6 mice treated with pristane (intraperitoneally, 3 months earlier) or thioglycolate (3 days earlier) or with untreated controls. EPs, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) mRNA expression was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). Cells were cultured unstimulated or stimulated with lipopolysaccharide (LPS) or LPS + interferon- in combination with EP subtype-specific agonists. Tumor necrosis factor (TNF-) and interleukin (IL)-6 production was tested by enzyme-linked immunosorbent assay (culture supernatant) and flow cytometry. TNF- mRNA levels also were examined. High levels of EPs (EP4/2>EP1>EP3), iNOS, and COX-2 mRNA were expressed in peritoneal macrophages from pristane-treated but not untreated or thioglycolate-treated mice (RT-PCR). TNF- production was inhibited 50–70% at 2–24 h by EP4/2 agonists, whereas IL-6 was enhanced up to 220%. TNF- inhibition is mediated partly via the protein kinase A pathway and partly via IL-6. Intracellular TNF- staining was inhibited 20% by EP4/2 agonists. TNF- mRNA levels were inhibited 50–70% at 2–24 h, indicating that TNF- inhibition was partly at the level of transcription. EP1/3 agonists had little effect. Synovial cells from mice with pristane-induced arthritis (DBA/1) also expressed EP2/4, and the EP2/4 agonist inhibited TNF- production. PGE₂ can modulate inflammatory reactions via the EP2/4 receptor through its regulation of TNF- and IL-6. Modification of EP signaling may be a new therapeutic strategy in inflammatory/autoimmune diseases.

Key Words: EP receptors • agonists • cytokines • pristane • arthritis

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