title: CD36 protein is involved in store-operated calcium flux, phospholipase A2 activation, and production of prostaglandin E2.
abstract: The scavenger receptor FAT/CD36 contributes to the inflammation associated with diabetes, atherosclerosis, thrombosis, and Alzheimer disease. Underlying mechanisms include CD36 promotion of oxidative stress and its signaling to stress kinases. Here we document an additional mechanism for the role of CD36 in inflammation. CD36 regulates membrane calcium influx in response to endoplasmic reticulum (ER) stress, release of arachidonic acid (AA) from cellular membranes by cytoplasmic phospholipase A(2)α (cPLA(2)α) and contributes to the generation of proinflammatory eicosanoids. CHO cells stably expressing human CD36 released severalfold more AA and prostaglandin E(2) (PGE(2)), a major product of AA metabolism by cyclooxygenases, in response to thapsigargin-induced ER stress as compared with control cells. Calcium influx after ER calcium release resulted in phosphorylation of cPLA(2) and its translocation to membranes in a CD36-dependent manner. Peritoneal macrophages from CD36(-/-) mice exhibited diminished calcium transients and reduced AA release after thapsigargin or UTP treatment with decreased ERK1/2 and cPLA(2) phosphorylation. However, PGE(2) production was unexpectedly enhanced in CD36(-/-) macrophages, which probably resulted from a large induction of cyclooxygenase 2 mRNA and protein. The data demonstrate participation of CD36 in membrane calcium influx in response to ER stress or purinergic receptor stimulation resulting in AA liberation for PGE(2) formation. Collectively, these results identify a mechanism contributing to the pleiotropic proinflammatory effects of CD36 and suggest that its targeted inhibition may reduce the acute inflammatory response.
authors: Department of Medicine, Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors: Ondrej
authors: O
authors: Kuda
authors: Christopher M
authors: CM
authors: Jenkins
authors: James R
authors: JR
authors: Skinner
authors: Sung Ho
authors: SH
authors: Moon
authors: Xiong
authors: X
authors: Su
authors: Richard W
authors: RW
authors: Gross
authors: Nada A
authors: NA
authors: Abumrad
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D054513:Group IV Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000494:pharmacology
chemical_list: D018955:CD36 Antigens; D004791:Enzyme Inhibitors; D019284:Thapsigargin; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054513:Group IV Phospholipases A2; D015232:Dinoprostone; D002118:Calcium; D014544:Uridine Triphosphate