title: Myeloid Cell Prostaglandin E2 Receptor EP4 Modulates Cytokine Production but Not Atherogenesis in a Mouse Model of Type 1 Diabetes.
abstract: Type 1 diabetes mellitus (T1DM) is associated with cardiovascular complications induced by atherosclerosis. Prostaglandin E2 (PGE2) is often raised in states of inflammation, including diabetes, and regulates inflammatory processes. In myeloid cells, a key cell type in atherosclerosis, PGE2 acts predominately through its Prostaglandin E Receptor 4 (EP4; Ptger4) to modulate inflammation. The effect of PGE2-mediated EP4 signaling specifically in myeloid cells on atherosclerosis in the presence and absence of diabetes is unknown. Because diabetes promotes atherosclerosis through increased arterial myeloid cell accumulation, we generated a myeloid cell-targeted EP4-deficient mouse model (EP4M-/-) of T1DM-accelerated atherogenesis to investigate the relationship between myeloid cell EP4, inflammatory phenotypes of myeloid cells, and atherogenesis. Diabetic mice exhibited elevated plasma PGE metabolite levels and elevated Ptger4 mRNA in macrophages, as compared with non-diabetic littermates. PGE2 increased Il6, Il1b, Il23 and Ccr7 mRNA while reducing Tnfa mRNA through EP4 in isolated myeloid cells. Consistently, the stimulatory effect of diabetes on peritoneal macrophage Il6 was mediated by PGE2-EP4, while PGE2-EP4 suppressed the effect of diabetes on Tnfa in these cells. In addition, diabetes exerted effects independent of myeloid cell EP4, including a reduction in macrophage Ccr7 levels and increased early atherogenesis characterized by relative lesional macrophage accumulation. These studies suggest that this mouse model of T1DM is associated with increased myeloid cell PGE2-EP4 signaling, which is required for the stimulatory effect of diabetes on IL-6, markedly blunts the effect of diabetes on TNF-α and does not modulate diabetes-accelerated atherogenesis.
authors.affiliation: Department of Medicine, UW Diabetes Institute, University of Washington, Seattle, WA 98109, United States of America.
authors.forename: Sara N
authors.initials: SN
authors.lastname: Vallerie
authors.affiliation: Department of Medicine, UW Diabetes Institute, University of Washington, Seattle, WA 98109, United States of America.
authors.forename: Farah
authors.initials: F
authors.lastname: Kramer
authors.affiliation: Department of Medicine, UW Diabetes Institute, University of Washington, Seattle, WA 98109, United States of America.
authors.forename: Shelley
authors.initials: S
authors.lastname: Barnhart
authors.affiliation: Department of Medicine, UW Diabetes Institute, University of Washington, Seattle, WA 98109, United States of America.
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Kanter
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN 37212, United States of America.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Breyer
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, United States of America.
authors.forename: Katrin I
authors.initials: KI
authors.lastname: Andreasson
authors.affiliation: Department of Medicine, UW Diabetes Institute, University of Washington, Seattle, WA 98109, United States of America.|Department of Pathology, UW Diabetes Institute, University of Washington, Seattle, WA 98109, United States of America.
authors.forename: Karin E
authors.initials: KE
authors.lastname: Bornfeldt
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism*; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C515371:Ccr7 protein, mouse; D007378:Interleukins; C545651:Ptger4 protein, mouse; D054400:Receptors, CCR7; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014409:Tumor Necrosis Factor-alpha; D015232:Dinoprostone