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• W2058703313 abstract "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-κB 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-κB 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. 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-κB 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-κB 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. During infection, acute inflammation, trauma, neoplastic growth, or any other tissue damage in general, the host undergoes a series of biochemical and physiological changes known as the acute phase response (APR), 3The abbreviations used are: APRacute phase responseHDLhigh density lipoproteinKCKupffer cellsLDLlow density lipoproteinMAPKmitogen-activated protein kinaseMEKMAPK kinaseoxLDLoxidized LDLPDTCpyrrolidine dithiocarbamateSAAserum amyloid AWTwild typeDMEMDulbecco's modified Eagle's mediumFCSfetal calf serumBSAbovine serum albuminFACSfluorescence-activated cell sorterLPSlipopolysaccharideJNKc-Jun N-terminal kinaseERKextracellular signal-regulated kinaseILinterleukinSR-BIscavenger receptor class B, type ITLRtoll-like receptorTNFtumor necrosis factorhCD36human CD36. a reaction that plays a critical role in the innate immune response to tissue injury (1.Kushner I. Rzewnicki D.L. Baillieres Clin. Rheumatol. 1994; 8: 513-530Abstract Full Text PDF PubMed Scopus (124) Google Scholar). APR features a cascade of events leading to the hepatic production of acute phase proteins that play an important role in the defense response of the host. Serum amyloid A (SAA), normally present in plasma in only trace amounts, is a major acute phase reactant, whose plasma levels may increase up to 1000-fold (1.Kushner I. Rzewnicki D.L. Baillieres Clin. Rheumatol. 1994; 8: 513-530Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 2.Kushner I. Ann. N.Y. Acad. Sci. 1982; 389: 39-48Crossref PubMed Scopus (1171) Google Scholar, 3.Uhlar C.M. Whitehead A.S. Eur. J. Biochem. 1999; 265: 501-523Crossref PubMed Scopus (893) Google Scholar) within hours in response to various insults. SAA is an amphipathic α-helical apolipoprotein that is transported in the circulation primarily in association with high density lipoprotein (HDL) (4.Malle E. Steinmetz A. Raynes J.G. Atherosclerosis. 1993; 102: 131-146Abstract Full Text PDF PubMed Scopus (176) Google Scholar, 5.Patel H. Fellowes R. Coade S. Woo P. Scand. J. Immunol. 1998; 48: 410-418Crossref PubMed Scopus (145) Google Scholar, 6.Coetzee G.A. Strachan A.F. van der Westhuyzen D.R. Hoppe H.C. Jeenah M.S. de Beer F.C. J. Biol. Chem. 1986; 261: 9644-9651Abstract Full Text PDF PubMed Google Scholar). Although acute phase SAA is predominantly expressed and produced by liver cells, there are growing numbers of reports describing its extrahepatic production by various tissues and cells. In humans, the expression and production of acute phase SAA have been found in several cell types within atherosclerotic lesions, including endothelial cells, macrophages, adipocytes, and smooth muscle cells (7.Meek R.L. Urieli-Shoval S. Benditt E.P. Proc. Natl. Acad. Sci. U.S.A. 1994; 91: 3186-3190Crossref PubMed Scopus (276) Google Scholar) as well as in the epithelial cells of several normal tissues (8.Urieli-Shoval S. Cohen P. Eisenberg S. Matzner Y.J. J. Histochem. Cytochem. 1998; 46: 1377-1384Crossref PubMed Scopus (183) Google Scholar). acute phase response high density lipoprotein Kupffer cells low density lipoprotein mitogen-activated protein kinase MAPK kinase oxidized LDL pyrrolidine dithiocarbamate serum amyloid A wild type Dulbecco's modified Eagle's medium fetal calf serum bovine serum albumin fluorescence-activated cell sorter lipopolysaccharide c-Jun N-terminal kinase extracellular signal-regulated kinase interleukin scavenger receptor class B, type I toll-like receptor tumor necrosis factor human CD36. In addition to its well established acute response to inflammatory stimuli, an SAA response can also be observed in some chronic inflammatory conditions. Thus, SAA was found to be expressed in the brains of patients with Alzheimer disease (9.Liang J.S. Sloane J.A. Wells J.M. Abraham C.R. Fine R.E. Sipe J.D. Neurosci. Lett. 1997; 225: 73-76Crossref PubMed Scopus (65) Google Scholar) and in synovial fibroblasts of rheumatoid arthritis patients (10.Kumon Y. Suehiro T. Hashimoto K. Nakatani K. Sipe J.D. J. Rheumatol. 1999; 26: 785-790PubMed Google Scholar). Multiple clinical studies have demonstrated a significant association of altered SAA levels with several pathological states, particularly chronic inflammatory diseases such as secondary amyloidosis (11.Pepys M.B. Baltz M.L. Adv. Immunol. 1983; 34: 141-212Crossref PubMed Scopus (1024) Google Scholar, 12.Husebekk A. Skogen B. Husby G. Marhaug G. Scand. J. Immunol. 1985; 21: 283-287Crossref PubMed Scopus (205) Google Scholar), atherosclerosis (13.Malle E. De Beer F.C. Eur. J. Clin. Invest. 1996; 26: 427-435Crossref PubMed Scopus (304) Google Scholar, 14.Fyfe A.I. Rothenberg L.S. DeBeer F.C. Cantor R.M. Rotter J.I. Lusis A.J. Circulation. 1997; 96: 2914-2919Crossref PubMed Scopus (117) Google Scholar), and rheumatoid arthritis (15.Chambers R.E. MacFarlane D.G. Whicher J.T. Dieppe P.A. Ann. Rheum. Dis. 1983; 42: 665-667Crossref PubMed Scopus (69) Google Scholar, 16.O'Hara R. Murphy E.P. Whitehead A.S. FitzGerald O. Bresnihan B. Arthritis Res. 2000; 2: 142-144Crossref PubMed Scopus (111) Google Scholar). In addition, SAA levels are increased in conditions associated with increased cardiovascular risk, including obesity (17.Leinonen E. Hurt-Camejo E. Wiklund O. Hultén L.M. Hiukka A. Taskinen M.R. Atherosclerosis. 2003; 166: 387-394Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar, 18.Jousilahti P. Salomaa V. Rasi V. Vahtera E. Palosuo T. Atherosclerosis. 2001; 156: 451-456Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar), insulin resistance (17.Leinonen E. Hurt-Camejo E. Wiklund O. Hultén L.M. Hiukka A. Taskinen M.R. Atherosclerosis. 2003; 166: 387-394Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar, 19.Ebeling P. Teppo A.M. Koistinen H.A. Viikari J. Rönnemaa T. Nissén M. Bergkulla S. Salmela P. Saltevo J. Koivisto V.A. Diabetologia. 1999; 42: 1433-1438Crossref PubMed Scopus (85) Google Scholar), metabolic syndrome (20.Leinonen E.S. Hiukka A. Hurt-Camejo E. Wiklund O. Sarna S.S. Mattson Hultén L. Westerbacka J. Salonen R.M. Salonen J.T. Taskinen M.R. J. Intern. Med. 2004; 256: 119-127Crossref PubMed Scopus (65) Google Scholar), and diabetes (17.Leinonen E. Hurt-Camejo E. Wiklund O. Hultén L.M. Hiukka A. Taskinen M.R. Atherosclerosis. 2003; 166: 387-394Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar, 19.Ebeling P. Teppo A.M. Koistinen H.A. Viikari J. Rönnemaa T. Nissén M. Bergkulla S. Salmela P. Saltevo J. Koivisto V.A. Diabetologia. 1999; 42: 1433-1438Crossref PubMed Scopus (85) Google Scholar, 21.Haffner S.M. Agostino Jr., R.D. Saad M.F. O'Leary D.H. Savage P.J. Rewers M. Selby J. Bergman R.N. Mykkänen L. Am. J. Cardiol. 2000; 85: 1395-1400Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). In vitro studies have suggested a number of pathways involving SAA in host defense mechanisms, inflammation, and atherogenesis. Lipid-poor SAA can act as a chemoattractant for inflammatory cells such as monocytes, polymorphonuclear leukocytes, and T-lymphocytes (22.Badolato R. Wang J.M. Murphy W.J. Lloyd A.R. Michiel D.F. Bausserman L.L. Kelvin D.J. Oppenheim J.J. J. Exp. Med. 1994; 180: 203-209Crossref PubMed Scopus (430) Google Scholar, 23.Xu L. Badolato R. Murphy W.J. Longo D.L. Anver M. Hale S. Oppenheim J.J. Wang J.M. J. Immunol. 1995; 155: 1184-1190PubMed Google Scholar), all of which are involved in host defense mechanisms. It has been reported that SAA significantly stimulates the secretion of pro-inflammatory cytokines by cultured human neutrophils, lymphocytes (24.Furlaneto C.J. Campa A. Biochem. Biophys. Res. Commun. 2000; 268: 405-408Crossref PubMed Scopus (193) Google Scholar), and THP-1 monocytic cells (5.Patel H. Fellowes R. Coade S. Woo P. Scand. J. Immunol. 1998; 48: 410-418Crossref PubMed Scopus (145) Google Scholar). SAA can act as opsonin for Gram-negative bacteria, thereby enhancing bacterial phagocytosis as well as bacterium-stimulated cytokine release by peripheral blood mononuclear cell-derived macrophages (25.Shah C. Hari-Dass R. Raynes J.G. Blood. 2006; 108: 1751-1757Crossref PubMed Scopus (164) Google Scholar). By displacing apoA-I from HDL (26.Husebekk A. Skogen B. Husby G. Scand. J. Immunol. 1987; 25: 375-381Crossref PubMed Scopus (47) Google Scholar), lipoprotein-associated SAA may play a role in redirecting HDL to the sites of tissue destruction and cholesterol accumulation (27.Kisilevsky R. Subrahmanyan L. Lab. Invest. 1992; 66: 778-785PubMed Google Scholar). In addition, non-HDL-associated SAA promotes cholesterol efflux by both ABCA1-dependent and -independent mechanisms (28.Stonik J.A. Remaley A.T. Demosky S.J. Neufeld E.B. Bocharov A. Brewer H.B. Biochem. Biophys. Res. Commun. 2004; 321: 936-941Crossref PubMed Scopus (68) Google Scholar). SAA may also contribute to HDL-mediated clearance of cellular cholesterol by modulating lecithin:cholesterol acyltransferase activity (29.Steinmetz A. Hocke G. Saïle R. Puchois P. Fruchart J.C. Biochim. Biophys. Acta. 1989; 1006: 173-178Crossref PubMed Scopus (112) Google Scholar) as well as by modulating cholesterol metabolism by serving as a cholesterol-binding protein (30.Liang J.S. Sipe J.D. J. Lipid Res. 1995; 36: 37-46Abstract Full Text PDF PubMed Google Scholar). The importance of SAA in various physiological and pathological processes has raised considerable interest in the identification of receptors that could potentially mediate binding/internalization and pro-inflammatory effects of SAA. Recent studies revealed several proteins that are capable of binding and/or mediating various SAA activities. FPRL1 (formyl peptide receptor like-1), a protein found in neutrophils, has been shown to mediate SAA-induced leukocyte chemotaxis (31.Su S.B. Gong W. Gao J.L. Shen W. Murphy P.M. Oppenheim J.J. Wang J.M. J. Exp. Med. 1999; 189: 395-402Crossref PubMed Scopus (374) Google Scholar) as well as release of cytokines and matrix metalloproteinase-9 from human leukocytes (32.Lee H.Y. Kim M.K. Park K.S. Bae Y.H. Yun J. Park J.I. Kwak J.Y. Bae Y.S. Biochem. Biophys. Res. Commun. 2005; 330: 989-998Crossref PubMed Scopus (115) Google Scholar). The scavenger receptor SR-BI has been demonstrated to mediate the cholesterol efflux function of HDL-associated SAA (33.van der Westhuyzen D.R. Cai L. de Beer M.C. de Beer F.C. J. Biol. Chem. 2005; 280: 35890-35895Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar), whereas its human orthologue CLA-1 has been shown to internalize and mediate the pro-inflammatory activity of lipid-poor SAA via MAPK signaling pathways (34.Baranova I.N. Vishnyakova T.G. Bocharov A.V. Kurlander R. Chen Z. Kimelman M.L. Remaley A.T. Csako G. Thomas F. Eggerman T.L. Patterson A.P. J. Biol. Chem. 2005; 280: 8031-8040Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar). Finally, recent experimental evidence suggests that toll-like receptors (TLRs) act as novel SAA receptors. TLR2 has been demonstrated to bind SAA and mediate SAA-stimulated pro-inflammatory cytokine expression in bone marrow-derived macrophages (35.Cheng N He R. Tian J. Ye P.P. Ye R.D. J. Immunol. 2008; 181: 22-26Crossref PubMed Scopus (226) Google Scholar), while functional TLR4 was shown to be required for SAA-induced NO production through the activation of ERK1/2 and p38 MAPKs in murine peritoneal macrophages (36.Sandri S. Rodriguez D. Gomes E. Monteiro H.P. Russo M. Campa A. J. Leukocyte Biol. 2008; 83: 1174-1180Crossref PubMed Scopus (149) Google Scholar). Both TLRs and scavenger receptors are abundantly expressed in mononuclear phagocyte lineage cell types and play an essential role in innate immunity as pattern recognition receptors capable of recognizing a broad range of molecular patterns commonly found on pathogens. A widely accepted concept is that ligand binding to scavenger receptors leads to endocytosis and lysosomal degradation (37.Krieger M. Acton S. Ashkenas J. Pearson A. Penman M. Resnick D. J. Biol. Chem. 1993; 268: 4569-4572Abstract Full Text PDF PubMed Google Scholar, 38.Pearson A.M. Curr. Opin. Immunol. 1996; 8: 20-28Crossref PubMed Scopus (250) Google Scholar), whereas engagement of TLRs transmits transmembrane signals to activate NF-κB and MAPK pathways (39.Muzio M. Natoli G. Saccani S. Levrero M. Mantovani A. J. Exp. Med. 1998; 187: 2097-2101Crossref PubMed Scopus (527) Google Scholar, 40.Faure E. Equils O. Sieling P.A. Thomas L. Zhang F.X. Kirschning C.J. Polentarutti N. Muzio M. Arditi M. J. Biol. Chem. 2000; 275: 11058-11063Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar, 41.Guha M. Mackman N. Cell. Signal. 2001; 13: 85-94Crossref PubMed Scopus (1980) Google Scholar). Microbial recognition, signaling, and modulation of TLR responses are known to require the presence of co-receptors/accessory molecules. By analogy with CD14 that is required for ligand recruitment to TLR4, recent findings demonstrated that scavenger receptor CD36 is an essential co-receptor involved in recognizing and presenting lipoteichoic acid and certain diacylglycerides to TLR2/6-mediated signaling pathways (42.Hoebe K. Georgel P. Rutschmann S. Du X. Mudd S. Crozat K. Sovath S. Shamel L. Hartung T. Zähringer U. Beutler B. Nature. 2005; 433: 523-527Crossref PubMed Scopus (709) Google Scholar, 43.Triantafilou M. Gamper F.G. Haston R.M. Mouratis M.A. Morath S. Hartung T. Triantafilou K. J. Biol. Chem. 2006; 281: 31002-31011Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar). At the same time, there is mounting evidence supporting an essential role of scavenger receptors as independent signaling molecules capable of activating signaling pathways upon ligand binding (44.Jiménez B. Volpert O.V. Reiher F. Chang L. Muñoz A. Karin M. Bouck N. Oncogene. 2001; 20: 3443-3448Crossref PubMed Scopus (80) Google Scholar, 45.Moore K.J. El Khoury J. Medeiros L.A. Terada K. Geula C. Luster A.D. Freeman M.W. J. Biol. Chem. 2002; 277: 47373-47379Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar, 46.Rahaman S.O. Lennon D.J. Febbraio M. Podrez E.A. Hazen S.L. Silverstein R.L. Cell Metab. 2006; 4: 211-221Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar). In our previous study (34.Baranova I.N. Vishnyakova T.G. Bocharov A.V. Kurlander R. Chen Z. Kimelman M.L. Remaley A.T. Csako G. Thomas F. Eggerman T.L. Patterson A.P. J. Biol. Chem. 2005; 280: 8031-8040Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar), we demonstrated that human class B scavenger receptor CLA-1 could function as an SAA signaling receptor, mediating its cytokine-like activity via a MAPK signaling pathway. CD36 is an 88-kDa double-spanning plasma membrane glycoprotein and a member of the class B scavenger receptor family. As a pattern recognition receptor, CD36, by analogy with CLA-1/SR-BI, binds a broad variety of ligands, including native, oxidized, and acetylated low density lipoprotein (LDL) (47.Febbraio M. Hajjar D.P. Silverstein R.L. J. Clin. Invest. 2001; 108: 785-791Crossref PubMed Scopus (933) Google Scholar, 48.Endemann G. Stanton L.W. Madden K.S. Bryant C.M. White R.T. Protter A.A. J. Biol. Chem. 1993; 268: 11811-11816Abstract Full Text PDF PubMed Google Scholar), anionic phospholipids (49.Rigotti A. Acton S.L. Krieger M. J. Biol. 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Science. 2005; 309: 1251-1253Crossref PubMed Scopus (304) Google Scholar, 54.Stuart L.M. Deng J. Silver J.M. Takahashi K. Tseng A.A. Hennessy E.J. Ezekowitz R.A. Moore K.J. J. Cell Biol. 2005; 170: 477-485Crossref PubMed Scopus (328) Google Scholar, 55.Baranova I.N. Kurlander R. Bocharov A.V. Vishnyakova T.G. Chen Z. Remaley A.T. Csako G. Patterson A.P. Eggerman T.L. J. Immunol. 2008; 181: 7147-7156Crossref PubMed Scopus (124) Google Scholar), as well as the structural components of their bacterial cell walls (42.Hoebe K. Georgel P. Rutschmann S. Du X. Mudd S. Crozat K. Sovath S. Shamel L. Hartung T. Zähringer U. Beutler B. Nature. 2005; 433: 523-527Crossref PubMed Scopus (709) Google Scholar, 54.Stuart L.M. Deng J. Silver J.M. Takahashi K. Tseng A.A. Hennessy E.J. Ezekowitz R.A. Moore K.J. J. Cell Biol. 2005; 170: 477-485Crossref PubMed Scopus (328) Google Scholar, 55.Baranova I.N. Kurlander R. Bocharov A.V. Vishnyakova T.G. Chen Z. Remaley A.T. Csako G. Patterson A.P. Eggerman T.L. J. Immunol. 2008; 181: 7147-7156Crossref PubMed Scopus (124) Google Scholar). Synthetic amphipathic peptides, possessing one or more class A amphipathic helices in their structure, have been earlier shown to be potent ligands for both CLA-1/SR-B1 and CD36 receptors (34.Baranova I.N. Vishnyakova T.G. Bocharov A.V. Kurlander R. Chen Z. Kimelman M.L. Remaley A.T. Csako G. Thomas F. Eggerman T.L. Patterson A.P. J. Biol. Chem. 2005; 280: 8031-8040Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 55.Baranova I.N. Kurlander R. Bocharov A.V. Vishnyakova T.G. Chen Z. Remaley A.T. Csako G. Patterson A.P. Eggerman T.L. J. Immunol. 2008; 181: 7147-7156Crossref PubMed Scopus (124) Google Scholar, 56.Schulthess G. Compassi S. Werder M. Han C.H. Phillips M.C. Hauser H. Biochemistry. 2000; 39: 12623-12631Crossref PubMed Scopus (42) Google Scholar). The discovery of the multiple ligands shared by these two scavenger receptors along with the fact that SAA is also known to be an amphipathic protein with two amphipathic α-helical regions in the 1–18 N-terminal and 72–86 C-terminal sequences (3.Uhlar C.M. Whitehead A.S. Eur. J. Biochem. 1999; 265: 501-523Crossref PubMed Scopus (893) Google Scholar) prompted us to investigate the potential role of CD36 as an SAA receptor for both uptake and signaling. All media, serum preparations, cell trackers, reactive fluorescent dyes and antibiotics were obtained from Invitrogen. Recombinant synthetic human apo-SAA was purchased from PeproTech (Rocky Hill, NJ). The lipid content of the recombinant apo-SAA was analyzed by the phospholipids B enzymatic method (Wako, Richmond, VA), and the cholesterol content was determined by an enzymatic cholesterol method on a Cobas Fara II analyzer (Roche Applied Science). These assays indicated that the SAA preparation contained only small amounts of phospholipids (5 ng/μg) and cholesterol (<2 ng/μg) and hence was considered as a lipid-poor form of SAA throughout this study. The endotoxin level in both SAA and HDL preparations was less than 0.1 ng per μg (1 EU/μg). The anti-CD36 monoclonal antibody FA16 was purchased from Abcam Inc. (Cambridge, MA). Anti-SAA polyclonal IgG was purified by affinity chromatography from a rabbit anti-recombinant human SAA serum obtained through Custom Polyclonal Antibody Service (Primm Biotech, Needham, MA). Synthetic amphipathic peptides were synthesized by a solid phase procedure (57.Merrifield R.B. JAMA. 1969; 210: 1247-1254Crossref PubMed Scopus (11) Google Scholar, 58.Fairwell T. Hospattankar A.V. Brewer Jr., H.B. Khan S.A. Proc. Natl. Acad. Sci. U.S.A. 1987; 84: 4796-4800Crossref PubMed Scopus (19) Google Scholar). Peptide sequences were described in a previous report (59.Bocharov A.V. Baranova I.N. Vishnyakova T.G. Remaley A.T. Csako G. Thomas F. Patterson A.P. Eggerman T.L. J. Biol. Chem. 2004; 279: 36072-36082Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). CD36-derived peptides were synthesized by the CBER/FDA Core Facility (Bethesda). Human HDL and LDL, as well as apolipoproteins A-I (apoA-I) and A-II (apoA-II), were purchased from EMD Biosciences (San Diego). Extensively oxidized LDL (oxLDL) was prepared by incubation with 5 μm CuSO4 at 37 °C for 24 h as described previously (60.Kunjathoor V.V. Febbraio M. Podrez E.A. Moore K.J. Andersson L. Koehn S. Rhee J.S. Silverstein R. Hoff H.F. Freeman M.W. J. Biol. Chem. 2002; 277: 49982-49988Abstract Full Text Full Text PDF PubMed Scopus (760) Google Scholar). The MAPK inhibitors PD98059, SB203580, SP600125 were purchased from EMD Biosciences. The NF-κB inhibitors, pyrrolidine dithiocarbamate (PDTC) and sulfasalasine, recombinant mouse macrophage colony-stimulating factor, granulocyte colony-stimulating factor, LPS from Salmonella enterica (serotype Minnesota), and Staphylococcus aureus LTA were purchased from Sigma. HeLa (Tet-Off) cells were transfected with FuGENE 6 (Roche Diagnostics) using the expression plasmid pTRE2 (Clontech), encoding a human CD36 protein (pTRE2-CD36). Cells were co-transfected with pTRE2-hCD36 and pTK-Pur (Clontech), using a 1:20 ratio, and selected with 400 μg/ml puromycin. Puromycin-resistant cells were screened for the expression of the human CD36 protein utilizing mouse anti-hCD36 antibody (Abcam, Cambridge, MA) in Western blotting. The HEK293 cell line was stably transfected with CD36 pIRES-hrGFP-2a plasmid (Stratagene, La Jolla, CA) followed by selecting cells with the highest green fluorescent protein expression. HeLa (Tet-Off) cells (Clontech), hCD36-overexpressing HeLa cells, as well as the human embryonic kidney cell line HEK293 (ATCC, Manassas, VA), both wild type and CD36-overexpressing, were grown in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal calf serum (FCS), 2 mm glutamine, 100 IU/ml penicillin, 100 μg/ml streptomycin, and 100 μg/ml G418 at 37 °C in a 5% CO2-humidified atmosphere. THP-1 cells, a human monocyte cell line (ATCC), were grown in RPMI 1640 medium supplemented with the same additives as indicated above. Rat cd36-null (cd36−/−) and wild type (cd36+/+) macrophages were isolated from bone marrow cells of spontaneously hypertensive Wistar-Kioto male rats (SHR/NCrl) and its control strain Wistar-Kyoto/NCrl (Charles River Laboratories, Wilmington, MA), respectively. Initial breeding pairs of cd36−/− mice were generously provided by Dr. K. Moore (Harvard Medical School, Lipid Metabolism Unit). Mice used in these studies were propagated by homozygous mating colonies and maintained at the National Institutes of Health pathogen-free animal facility. Murine cd36−/− and cd36+/+ macrophages were isolated from bone marrow cells of CD36 null and control wild type mice, respectively. The macrophages were differentiated by culturing in RPMI 1640 medium, 20% FCS, in the presence of 10 ng/ml mouse macrophage colony-stimulating factor and 10 ng/ml mouse IL-4 for 7–10 days. Bone marrow-derived dendritic cells were generated from primary cultures of femoral marrow by culturing in the presence of 10 ng/ml mouse recombinant granulocyte colony-stimulating factor for 7–10 days. Kupffer cells (KC) were isolated from livers of CD36-deficient and normal rats using the method described by Smedsrød et al. (61.Smedsr⊘d B. Pertoft H. Eggertsen G. Sundström C. Cell Tissue Res. 1985; 241: 639-649PubMed Google Scholar), with some modifications (62.Zaĭtseva E.V. Khung Veĭ Vishniakova T.G. Frolova E.G. Repin V.S. Bocharov A.V. Biull. Eksp. Biol. Med. 1994; 117: 268-270Crossref PubMed Scopus (0) Google Scholar), using OptiPrep Density gradient reagent (Sigma) instead of Percoll for density gradient centrifugation. In brief, the liver was perfused with 500 ml of Ca2+/Mg2+-free Hanks' balanced salt solution followed by the perfusion with 50 ml of 0.05% collagenase type H (Invitrogen) in Mg2+-free Hanks' balanced salt solution containing 5 μm CaCl2. Hepatocytes were sedimented by repetitive centrifugations for 3 min at 50 × g in ice-cold Hanks' balanced salt solution. Supernatants containing sinusoidal nonparenchymal liver cells were collected and centrifuged for 5 min at 300 × g. Pelleted sinusoidal nonparenchymal liver cells were resuspended in 18% of OptiPrep density gradient reagent in Hanks' balanced salt solution and centrifuged at 1500 × g for 20 min. The sinusoidal nonparenchymal liver cells, banded at the top of the supernatant, were collected and pelleted by additional centrifugation for 5 min at 300 × g. The sinusoidal nonparenchymal liver cells suspension was plated in serum-free DMEM into 96-well culture plates for 15 min to allow KC to attach and spread. Nonattached cells were removed from the culture plates by extensive washing, and the KC were further cultivated in RPMI 1640 medium containing 10% FCS and 10 ng/ml macrophage colony-stimulating factor. SAA, native and oxidized lipoproteins, apoA-I, apoA-II, L3D-37pA, and BSA were conjugated with Alexa Fluor® 488, using a protein labeling kit (Invitrogen) following the vendor's instructions. HeLa cells were incubated with fluoro-labeled ligands at 37 °C for 1 h and then washed extensively with phosphate-buffered saline, detached with Cellstripper dissociation solution (Mediatech, Herndon, VA), fixed with 4% paraformaldehyde, and analyzed by a fluorescence-activated cell sorter (FACS, model A; Hitachi). CD36-overexpressing HeLa cells grown in 24-well plates were incubated with 5 μg/ml Alexa Fluor 488 SAA without or with increasing concentrations of unlabeled ligands at 37 °C for 2 h, then washed three times with phosphate-buffered saline, and detached from the plate surface by incubation in 200 μl of Cellstripper solution for 30 min at room temperature with continuous rocking on Rocker II (Boekel Scientific). Aliquots of cell suspension were transferred into 96-well black microplates and were read in a fluorescence plate reader (Wallac Victor 1420 Multilabel Counter, PerkinElmer Life Sciences). The recombinant human SAA preparation was iodinated by the Iodogen method (Pierce) to a specific activity of 200–300 cpm/ng protein. Confluent HeLa cells, mock-transfected and CD36-overexpressing, grown on 24-well plates were incubated in serum-free DMEM for 24 h prior to the onset of the assay. Saturation" @default.
• W2058703313 created "2016-06-24" @default.
• W2058703313 creator A5005077693 @default.
• W2058703313 creator A5010241534 @default.
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• W2058703313 date "2010-03-01" @default.
• W2058703313 modified "2023-10-18" @default.
• W2058703313 title "CD36 Is a Novel Serum Amyloid A (SAA) Receptor Mediating SAA Binding and SAA-induced Signaling in Human and Rodent Cells" @default.
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