Prostaglandin E2–EP4 signaling promotes immune inflammation through TH1 cell differentiation and TH17 cell expansion

• Published in: Nature medicine Vol. 15; no. 6; pp. 633 - 640
• Main Authors: Yao, Chengcan, Sakata, Daiji, Esaki, Yoshiyasu, Li, Youxian, Matsuoka, Toshiyuki, Kuroiwa, Kenji, Sugimoto, Yukihiko, Narumiya, Shuh
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2009; Nature Publishing Group
• Subjects: Animal models; Animals; Autoimmune diseases; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell differentiation; Cell Differentiation - immunology; Cell growth; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dermatitis, Contact - immunology; Dinoprostone - immunology; Dinoprostone - metabolism; Encephalomyelitis, Autoimmune, Experimental - immunology; Hypersensitivity; Immune system; Infectious Diseases; Inflammation - immunology; Inflammation - metabolism; Interleukin-17 - immunology; Interleukin-23 - biosynthesis; Interleukin-23 - immunology; Lipids; Lymph nodes; Lymphocytes; Metabolic Diseases; Mice; Molecular Medicine; Neurosciences; Proteins; Receptors, Prostaglandin E - immunology; Receptors, Prostaglandin E - metabolism; Receptors, Prostaglandin E, EP4 Subtype; Rheumatoid arthritis; Signal Transduction - immunology; Skin diseases; Th1 Cells - immunology; Th1 Cells - metabolism
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.1968

Prostaglandins play a key role in inflammation in a variety of settings. Now, Shuh Narumiya and colleagues show that prostaglandin E2 drives the production of inflammatory T helper cells, and that this can be blocked by inhibiting its EP4 receptor subtype. EP4 inhibitors were also effective at inhibiting disease pathogenesis in animal models of two inflammatory diseases. Two distinct helper T (T H ) subsets, T H 1 and T H 17, mediate tissue damage and inflammation in animal models of various immune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases and allergic skin disorders. These experimental findings, and the implication of these T H subsets in human diseases, suggest the need for pharmacological measures to manipulate these T H subsets. Here we show that prostaglandin E 2 (PGE 2 ) acting on its receptor EP4 on T cells and dendritic cells not only facilitates T H 1 cell differentiation but also amplifies interleukin-23–mediated T H 17 cell expansion in vitro . Administration of an EP4-selective antagonist in vivo decreases accumulation of both T H 1 and T H 17 cells in regional lymph nodes and suppresses the disease progression in mice subjected to experimental autoimmune encephalomyelitis or contact hypersensitivity. Thus, PGE 2 -EP4 signaling promotes immune inflammation through T H 1 differentiation and T H 17 expansion, and EP4 antagonism may be therapeutically useful for various immune diseases.