CD36 is a novel serum amyloid A (SAA) receptor mediating SAA binding and SAA-induced signaling in human and rodent cells.
Serum amyloid A (SAA) is a major acute phase protein involved in multiple physiological and pathological processes. This study provides experimental evidence that CD36, a phagocyte class B scavenger receptor, functions as a novel SAA receptor mediating SAA proinflammatory activity. The uptake of Alexa Fluor 488 SAA as well as of other well established CD36 ligands was increased 5-10-fold in HeLa cells stably transfected with CD36 when compared with mock-transfected cells. Unlike other apolipoproteins that bind to CD36, only SAA induced a 10-50-fold increase of interleukin-8 secretion in CD36-overexpressing HEK293 cells when compared with control cells. SAA-mediated effects were thermolabile, inhibitable by anti-SAA antibody, and also neutralized by association with high density lipoprotein but not by association with bovine serum albumin. SAA-induced cell activation was inhibited by a CD36 peptide based on the CD36 hexarelin-binding site but not by a peptide based on the thrombospondin-1-binding site. A pronounced reduction (up to 60-75%) of SAA-induced pro-inflammatory cytokine secretion was observed in cd36(-/-) rat macrophages and Kupffer cells when compared with wild type rat cells. The results of the MAPK phosphorylation assay as well as of the studies with NF-kappaB and MAPK inhibitors revealed that two MAPKs, JNK and to a lesser extent ERK1/2, primarily contribute to elevated cytokine production in CD36-overexpressing HEK293 cells. In macrophages, four signaling pathways involving NF-kappaB and three MAPKs all appeared to contribute to SAA-induced cytokine release. These observations indicate that CD36 is a receptor mediating SAA binding and SAA-induced pro-inflammatory cytokine secretion predominantly through JNK- and ERK1/2-mediated signaling.
Baranova
Irina N
IN
Department of Laboratory Medicine, Clinical Center, NICHD,National Institutes of Health, Bethesda, Maryland, USA.
Bocharov
Alexander V
AV
Vishnyakova
Tatyana G
TG
Kurlander
Roger
R
Chen
Zhigang
Z
Fu
Dong
D
Arias
Irwin M
IM
Csako
Gyorgy
G
Patterson
Amy P
AP
Eggerman
Thomas L
TL
D000818:Animals; D001665:Binding Sites; D018955:CD36 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005456:Fluorescent Dyes; D006367:HeLa Cells; D006801:Humans; D007457:Iodine Radioisotopes; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007668:Kidney / Q000166:cytology; D007728:Kupffer Cells / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009842:Oligopeptides / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D017434:Protein Structure, Tertiary; D051381:Rats; D011921:Rats, Inbred WKY; D000685:Serum Amyloid A Protein / Q000378:metabolism*; D019700:Thrombospondin 1 / Q000378:metabolism; D014162:Transfection
D018955:CD36 Antigens; C008132:Cd36 protein, rat; D005456:Fluorescent Dyes; D007457:Iodine Radioisotopes; D009842:Oligopeptides; D000685:Serum Amyloid A Protein; D019700:Thrombospondin 1; C086184:hexarelin; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases