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PubMed1993

Expression of thrombospondin (TSP1) and its receptors (CD36 and CD51) in normal, hyperplastic, and neoplastic human breast.

We have previously shown that thrombospondin (TSP) is present in normal breast secretions, and high levels of TSP are observed in malignant breast secretions and cytosols. Three genes encoding for three distinct TSPs (TSP1, TSP2, TSP3) have recently been described. In this study, using both immunohistochemistry and in situ hybridization, we report on the distribution of TSP1 in normal, hyperplastic, and neoplastic human breast. Its immunolocalization was also compared with that of two known cell surface receptors for TSP1: CD36 and CD51. In nonlactating ducts of normal and hyperplastic breast, TSP1 and CD51 are expressed in the basement membrane and in the basal surface of myoepithelial cells, respectively. In lactating adenomas, both TSP1 and CD51 disappear from the myoepithelial-stromal junction of ducts. However, TSP1 becomes selectively expressed at the apices of secretory epithelial cells of lactating ducts together with CD36, suggesting that the distribution of TSP1 and the appearance of its receptors are dependent on the secretory activity of human mammary ducts. In neoplastic human breast, a strong immunostaining for TSP1 is observed in the basement membrane surrounding in situ carcinomas (preinvasive cancer), and excessive TSP1 deposits are also observed in desmoplasia of invasive ductal carcinomas. TSP1 mRNA is localized in myoepithelial cells surrounding in situ carcinomas and in fibroblasts present in desmoplastic areas. On the other hand, few invasive ductal carcinoma cells (10%) express TSP1, while CD51 is moderately expressed by some neoplastic clusters, and no immunoreactivity is observed for CD36. By contrast, TSP1 is codistributed with CD51 in most of the invasive lobular carcinoma cells (40 to 80%) and with CD36 in a subpopulation (30 to 40%) of these invasive tumor cells. As previously observed with lactating adenomas, it is likely that the coexpression of TSP1 and CD36 is related to the secretory activity of invasive lobular carcinoma cells. The different distribution of TSP1 in invasive ductal versus lobular carcinomas may well reflect biological differences between these two main types of breast carcinoma. In this regard, the coexpression of TSP1 and CD36 may, in part at least, account for the variably invasive behavior of lobular carcinoma cells.

Amino Acid Sequence↗
PubMed1997

Identification of a region of PfEMP1 that mediates adherence of Plasmodium falciparum infected erythrocytes to CD36: conserved function with variant sequence.

Adherence of mature parasitized erythrocytes (PE) of Plasmodium falciparum to microvascular endothelial cells contributes directly to the virulence and pathology of this human malaria. The malarial variant antigen, P falciparum erythrocyte membrane protein 1 (PfEMP1), has been implicated as the PE receptor for CD36 on endothelial cells. We identified the region of PfEMP1 that mediates adherence of PE to CD36 and showed that a recombinant protein fragment from this region blocked and reversed adherence of antigenically different parasites. Sequence variation was evident in the CD36 binding domain of different PfEMP1 genes, yet many highly conserved residues, particularly cysteine residues, are evident. This suggests a highly conserved shape that mediates adherence to CD36. Immunization with the CD36-binding domain elicited sera that are cross-reactive with the different recombinant proteins but are strain-specific for the PE surface. Novel anti-adherence therapeutics and a malaria vaccine may derived from exploitation of the structure of the CD36 binding domain of PfEMP1.

Amino Acid Sequence↗
PubMed1998

Human platelet CD36 (GPIIIb, GPIV) binds to cholesteryl-hemisuccinate and can be purified by a simple two-step method making use of this property.

CD36, also known as GPIIIb or GPIV, is a main protein of the platelet membrane. Accumulating evidence implicates CD36 in the pathogenesis of atherosclerosis. CD36 binds to cholesteryl-hemisuccinate coupled to agarose. This binding may be of physiologic relevance since CD36 has a long extracellular hydrophobic region at its N-terminus and belongs to a family of proteins involved in lipid metabolism. This newly discovered binding property of CD36 was used to develop a rapid, efficient and gentle two-step purification method for CD36 from human platelets.

Blood Platelets↗
PubMed2003

Phospholipids in oxidized LDL not adducted to apoB are recognized by the CD36 scavenger receptor.

Previous studies have shown that oxidation of low-density lipoprotein (oxLDL) results in its recognition by scavenger receptors on macrophages. Whereas blockage of lysyl residues on apoB-100 of oxLDL by lipid peroxidation products appears to be critical for recognition by the scavenger receptor class A (SR-A), modification of the lipid moiety has been suggested to be responsible for recognition by the scavenger class B receptor, CD36. We studied the recognition by scavenger receptors of oxidized LDL in which lysyl residues are blocked prior to oxidation through methylation [ox(m)LDL]. This permits us to minimize any contribution of modified apoB-100 to the recognition of oxLDL, but does not disrupt the native configuration of lipids in the particle. We found that ox(m)LDL was recognized by receptors on mouse peritoneal macrophages (MPM) almost as well as oxLDL. Ox(m)LDL was recognized by CD36-transfected cells but not by SR-A-transfected cells. Oxidized phospholipids (oxPC) transferred from oxLDL or directly from oxPC to LDL, conveyed recognition by CD36-transfected cells, confirming that CD36 recognized unbound oxidized phospholipids in ox(m)LDL. Collectively, these results suggest that oxPC not adducted to apoB within the intact oxLDL particle are recognized by the macrophage scavenger receptor CD36, that these lipids are not recognized by SR-A, and that they can transfer from oxidized to unoxidized LDL and induce CD36 recognition.

Animals↗
PubMed1995

N-3 but not N-6 fatty acids reduce the expression of the combined adhesion and scavenger receptor CD36 in human monocytic cells.

CD36, a multifunctional adhesion receptor e.g. for thrombospondin and collagen, as well as a scavenger receptor for oxidized low density lipoprotein, is expressed e.g. on platelets and monocytes. By this dual role it might be involved in early steps of atherosclerosis like the recruitment of monocytes and formation of foam cells. We therefore studied the effects of n-3 fatty acids on CD36 expression in human monocytic cells. Incorporation of eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3) into cellular phospholipids resulted in a significant reduction of CD36 expression at the mRNA and protein level, whereas arachidonic acid (AA, C20: 4n-6) and linoleic acid (LA, C18:2n-6) tended to increase CD36 expression compared to the control. This specific down-regulation of CD36 by n-3 fatty acids in cells involved in the initiation and progression of atherogenesis and inflammation, represents a further mechanism that may contribute to the beneficial effects of n-3 polyunsaturated fatty acids (PUFA) in these disorders.

Arachidonic Acid↗
PubMed2002

Dissociation of apoptosis induction and CD36 upregulation by enzymatically modified low-density lipoprotein in monocytic cells.

Modified low-density lipoprotein (LDL) has been implicated as an initiating or amplifying factor in atherogenesis. Some of its biological activities, such as apoptosis induction and upregulation of the scavenger receptor CD36, appear to share common signaling pathways in cells of the cardiovascular system. Exposure of low-differentiated monocytic cells to LDL modified with 15-lipoxygenase and secretory phospholipase A(2) induced apoptosis and upregulated CD36. Cell treatment with constituents of modified LDL, such as 13-hydroxyoctadecadienoic acid (13-HODE), 25-hydroxycholesterol, and lysophosphatidyl choline, and with an unrelated apoptogen (TNF-related apoptosis-inducing ligand) induced apoptosis. In contrast, only 13-HODE caused upregulation of CD36 expression. Cotreatment with the pan-caspase inhibitor z.VAD-fmk resulted in suppression of apoptosis, but was without any effect on CD36 expression. These data indicate that in monocytic cells enzymatically modified LDL is capable of inducing both apoptosis and upregulation of CD36 expression. However, in our cellular model, the two induction processes appear to be causally unrelated.

Apoptosis↗
PubMed1994

Plasmodium falciparum: pfalhesin and CD36 form an adhesin/receptor pair that is responsible for the pH-dependent portion of cytoadherence/sequestration.

The cytoadherent behavior of two Plasmodium falciparum (human malaria) cell lines, FCR-3 and ITO4 (a cell line with elevated ICAM-1 adherence), was studied using CHO cells transfected with CD36 or ICAM-1 receptors as target cells. ICAM-1-mediated adherence was found to be relatively pH insensitive, whereas CD36-mediated adherence was pH sensitive and inhibited by monoclonal antibodies and peptides based on a region found in human band 3 protein and named pfalhesin. Immobilized pfalhesin was used as an affinity matrix to purify CD36 from extracts of C32 amelanotic melanoma cells, which have ICAM-1 as well as CD36 receptors, and bind both parasite cell lines. We conclude that pfalhesin and CD36 constitute an adhesin/receptor pair.

Amino Acid Sequence↗
PubMed1993

Gene encoding the collagen type I and thrombospondin receptor CD36 is located on chromosome 7q11.2.

The human CD36 is a member of a gene family of structurally related glycoproteins and functions as a receptor for collagen type I and thrombospondin. CD36 also binds to red blood cells infected with the human malaria parasite Plasmodium falciparum. In the present study, the CD36 gene was assigned to chromosome 7 by using the polymerase chain reaction with DNA from human-hamster somatic cell hybrids. Furthermore, the use of a CD36 genomic probe has allowed the localization of the CD36 locus to the 7q11.2 band by fluorescence in situ hybridization coupled with GTG-banding.

Amino Acid Sequence↗
PubMed1998

Differential expression of CD14, CD36 and the LDL receptor on human monocyte-derived macrophages. A novel cell culture system to study macrophage differentiation and heterogeneity.

Macrophages are key players in many aspects of human physiology and disease. It has been hypothesized that in a given microenvironment monocytes differentiate into specific subpopulations with distinct functions. In order to study the role of macrophage heterogeneity in atherogenesis, we established a novel isolation and culture technique for human monocyte-derived macrophages. The present technique does not select for monocyte subpopulations prior to the onset of differentiation. Monocytes were cultured for 2 weeks in the presence of autologous lymphocytes before being plated quantitatively. They differentiated into mature macrophages in terms of morphology, lipid composition, and biological activity. Based on phagocytic activity as well as on the expression of CD14, CD36, and the low-density lipoprotein (LDL) receptor, we have identified macrophage subpopulations that may play distinct roles in atherogenesis. While virtually all adherence-purified monocytes expressed CD14, CD36, and the LDL-R, we characterized three subpopulations of macrophages based on the expression of these antigens: CD36+CD14-LDL-R-(58+/-12%), CD36+CD14+LDL-R+(18+/-5%), the remaining cells being CD36-CD14- LDL-R-. The first two subsets decreased in size during further differentiation (51+/-12% and 8+/-3%, respectively). Our culture technique may also serve as a good model for studying the implications of macrophage heterogeneity in diseases other than atherosclerosis.

Antigens, CD↗
PubMed1994

Expression of the myelomonocytic antigens CD36 and L1 by keratinocytes in squamous intraepithelial lesions of the cervix.

The keratinocytes in squamous intraepithelial lesions (SILs) of the cervix show altered expression of a number of molecules involved both in the control of growth and differentiation and in cell surface interactions, particularly with components of the immune system. We have used tissue biopsies and in vitro model systems to investigate the expression in SILs of the molecules CD36 and L1, which are predominantly expressed by myelomonocytic cells but which also have functional roles in keratinocyte biology. Whereas the L1 protein (defined by the monoclonal antibody Mac387) was expressed by suprabasal and superficial cells in 12 of 12 cases of normal cervix (NCx) and in 14 of 14 cases of low-grade SILs (LG-SILs), in two of 16 cases of high-grade SILs (HG-SILs) it was entirely absent and in the remainder it was restricted to the most superficial layers. When an arbitrary grading scale was applied, L1 expression in HG-SILs proved to be significantly lower than in LG-SILs (P < .01) or in cases of NCx (P < .01). CD36 was expressed by superficial cells in four of 12 cases of NCx, in six of 14 LG-SILs, and none of 16 cases of HG-SILs (when graded, LG-SILs v HG-SILs = P < .05). The mechanisms underlying the expression of both molecules were investigated by growth in organotypic tissue culture of normal ectocervical epithelium and the cervical keratinocyte cell lines W12 (a model for LG-SILs) and CaSki and SiHa (models for HG-SILs). L1 was diffusely expressed by NCx cells and the W12 cell line, although its expression in the CaSki and SiHa cell lines was much more irregular and restricted. CD36 was occasionally present on the surface of superficial NCx and W12 cells, but was absent from CaSki and SiHa cells. Neither molecule could be induced by treatment of the cells with interferon-gamma. These data suggest that the expression of CD36 and L1 by cervical keratinocytes is related to their differentiation status rather than representing an effect of exogenous factors, such as those released by the immune cell infiltrate associated with SILs. CD36 may function as an immunoregulatory molecule on cervical keratinocytes in SILs, while L1 is more likely to be involved in the intracellular regulation of cell proliferation and maturation.

Antigens, CD↗
PubMed2006

Ceramides reduce CD36 cell surface expression and oxidised LDL uptake by monocytes and macrophages.

Oxidised LDL accumulates in macrophages following scavenger receptor (SR) uptake. The expression of the SR, CD36, is increased by oxidised LDL. The signalling molecule, ceramide, can modulate intracellular peroxides and increase lipid peroxidation. Ceramide also accumulates in atherosclerotic plaques. Thus, we have examined whether ceramide can modulate CD36 expression and function in human monocyte/macrophages. Addition of synthetic short chain ceramides or the action of sphingomyelinase to generate physiological long chain ceramides in situ caused significant reductions in CD36 expression by monocytes/macrophages which was not due to inhibition of mRNA expression. Inhibition of proteasomal degradation using lactacystin had no effect on CD36 expression, however, flow cytometric analysis of permeabilised cells suggested an intracellular trafficking blockade. Ceramide treated monocytes/macrophages showed dose dependent reduction in oxidised LDL uptake. Taken together, it is suggested that ceramide blocks the transport of CD36 to the membrane of monocytes/macrophages, thereby preventing uptake of oxidised LDL.

Acetylcysteine↗
PubMed2004

Antiatherogenic effect of Pistacia lentiscus via GSH restoration and downregulation of CD36 mRNA expression.

Pistacia lentiscus var. Chia (Anacardiaceae) grows almost exclusively on Chios Island, Greece, and gives a resinous exudate resin used for culinary purposes by Mediterranean people. We investigated the molecular mechanisms through which total polar extract of the resin inhibits oxidized low-density lipoprotein (oxLDL) cytotoxic effect on peripheral blood mononuclear cell (PBMC). Cells exposed to oxLDL underwent apoptosis and necrosis, dependent on the duration of exposure. When culturing cells with oxLDL and the polar extract concurrently, we observed inhibition of both the phenomena. Because under oxidative stress the pro-oxidant systems outbalance the antioxidant, potentially producing oxidative damage and ultimately leading to cell death, we measured the levels of intracellular antioxidant glutathione (GSH). Additionally, we measured CD36 expression, a class B scavenger receptor, on CD14-positive cells, as CD36 has been identified as the oxLDL receptor in macrophages and may play a pivotal role in atherosclerotic foam cell formation. oxLDL decreased GSH levels and upregulated CD36 expression. P. lentiscus extract restored GSH levels and downregulated CD36 expression, even at the mRNA level. In order to find out the biologically drastic constituents of the resin's polar extract, fractions derived from RP-HPLC analysis were examined for their antioxidant effect on oxidatively stressed PBMC. The triterpenoid fraction revealed remarkable increase in intracellular GSH. We suggest GSH restoration and downregulation of CD36 mRNA expression as the pathways via which P. lentiscus triterpenes exert antioxidant/antiatherogenic effect. Additionally, our results provide strong evidence of the resin's antiatherogenic effect; therefore it is credited with beneficial health aspects.

Antioxidants↗
PubMed2006

Cholesteryl ester hydroperoxides increase macrophage CD36 gene expression via PPARalpha.

The uptake of oxidized LDL by macrophages is a key event in the development of atherosclerosis. The scavenger receptor CD36 is one major receptor that internalizes oxidized LDL. In differentiated human macrophages, we compared the regulation of CD36 expression by copper-oxidized LDL or their products. Only oxidized derivatives of cholesteryl ester (CEOOH) increased the amount of CD36 mRNA (2.5-fold). Both oxidized LDL and CEOOH treatment increased two to fourfold the transcription of promoters containing peroxisome-proliferator-activated-receptor responsive elements (PPRE) in the presence of PPARalpha or gamma. Electrophoretic-mobility-shift-assays with nuclear extracts prepared from macrophages treated by either oxidized LDL or CEOOH showed increased binding of PPARalpha to the CD36 gene promoter PPRE. In conclusion, CEOOH present in oxidized LDL increase CD36 gene expression in a pathway involving PPARalpha.

CD36 Antigens↗
PubMed2004

The antiangiogenic effect of thrombospondin-2 is mediated by CD36 and modulated by histidine-rich glycoprotein.

Thrombospondins-1 and -2 (TSP-1, TSP-2) are matricellular glycoproteins with potent antiangiogenic activity. We have previously shown that the antiangiogenic activity of TSP-1 is mediated by the interaction of the type I repeats (TSR) with the receptor CD36, although other domains of TSP-1 have also been implicated. We now show that the antiangiogenic activity of TSP-2, which contains three TSRs but, unlike TSP-1, lacks the capacity to activate TGF-beta, is similarly dependent on CD36. Using the corneal pocket assay we found that TSP-2 did not inhibit bFGF-induced angiogenesis in CD36 null mice. We then demonstrated that (125)[I]-TSP-2 bound to murine macrophages and that binding was diminished by 70% by anti-CD36 antibody or by using cells from CD36 null animals. Solid-phase binding studies revealed that (125)[I]-TSP-2 bound to CD36/glutathione-S-transferase (GST) fusion proteins encoding the region spanning amino acids 93-120, but not amino acids 298-439. This 93-120 amino acid region, previously identified as the TSP-1 binding site, is homologous to domains on other TSP binding proteins, such as LIMP-2 and histidine-rich glycoprotein (HRGP). Finally, we showed with an immunoabsorbent binding assay that TSP-2 bound HRGP with high affinity and that HRGP blocked the antiangiogenic activity of TSP-2, acting like a "decoy" receptor. These data suggest that modulation of the TSR/CD36 system may play an important role in the regulation of the angiogenic "switch," and may provide a target for therapeutic interventions.

Angiogenesis Inhibitors↗
PubMed2004

Chemical modifications of band 3 protein affect the adhesion of Plasmodium falciparum-infected erythrocytes to CD36.

The role of the erythrocyte anion exchanger, band 3 protein (AE1), in the adhesion of Plasmodium falciparum-infected erythrocytes to CD36 and thrombospondin (TSP) was studied. Two specific anion exchange inhibitors that bind covalently to different regions of the band 3 molecule affected cytoadherence in dissimilar ways. Modification of lysine 539 by diisothiocyanostilbene sulfonic acid (DIDS) resulted in a significant reduction in the adhesive properties of parasitized erythrocytes for CD36, but not TSP, whereas treatment with fluorescein-5-maleimide, which modifies lysine 430, was without effect on both TSP and CD36 binding. The adhesive properties of the DIDS binding region (DBR) was demonstrated by competition experiments using synthetic peptides and by direct interaction of such peptides with CD36 transfected CHO cells. The results suggest that host membrane proteins such as AE1 contribute to the adhesion of malaria-infected erythrocytes to CD36.

Amino Acid Sequence↗
PubMed2006

The leukocyte expression of CD36 is low in patients with Alzheimer's disease and mild cognitive impairment.

CD36, a scavenger receptor of class B (SR-B), helps mediate microglial and macrophage response to beta-amyloid fibrils (betaA), and seems to play a key role in the proinflammatory events associated with Alzheimer disease (AD) in many tissues. Peripheral leukocytes express many molecules and multiple receptors which undergo the same regulatory mechanisms as those operative in the brain. Thus, these cells, easily obtainable through peripheral blood sampling, may be used as a tool to investigate changes occurring in inaccessible brain areas. Based on these premises, we investigated the leukocyte expression of CD36 in 70 AD patients and in 30 subjects with mild cognitive impairment (MCI). Results were compared to those of 20 young and 40 age-matched control subjects. Leukocyte expression of CD36 was significantly reduced versus controls in both AD and MCI patients, while in young and old controls there were no age-related changes. Although preliminary, these data indicate that the reduction of CD36 expression in leukocytes is a disease-related phenomenon, occurring since the early stages of AD (MCI). Irrespective of the mechanism(s) underlying such changes, assessment of leukocyte CD36 expression might represent an useful tool to support the diagnosis of AD and to screen MCI patients candidates to develop the disease.

Adult↗
PubMed2002

Adipocytes recognize and degrade oxidized low density lipoprotein through CD36.

CD36 expressed on adipocytes is thought to function as a fatty acid transporter (FAT). Here we report that adipocytes can endocytose and lysosomally degrade OxLDL, mainly mediated by CD36. Mouse 3T3-L1 preadipocytes showed marked increase in uptake and degradation of (125)I-OxLDL during their differentiation to adipocytes. RT-PCR and immunoblot analysis indicated that expression of CD36 but not of scavenger receptor class A or macrosialin is required for the increase in uptake and degradation of (125)I-OxLDL in 3T3-L1 cells. An anti-CD36 antibody inhibited both uptake and degradation activities of (125)I-OxLDL up to 60%. These results strongly suggest that adipocytes may function as phagocytes like macrophages and that CD36 plays a novel role in adipose tissues.

3T3 Cells↗
PubMed1993

Structural study of the sugar chains of CD36 purified from bovine mammary epithelial cells: occurrence of novel hybrid-type sugar chains containing the Neu5Ac alpha 2-->6GalNAc beta 1-->4GlcNAc and the Man alpha 1-->2Man alpha 1-->3Man alpha 1-->6Man groups.

CD36 is a glycoprotein included in the bovine milk fat globule membrane derived from mammary secretory epithelial cells during lactation. Asparagine-linked sugar chains were quantitatively released from CD36 as oligosaccharides by hydrazinolysis. These sugar chains were converted to radioactive oligosaccharides by reduction with NaB3H4 and separated into neutral and acidic fractions by paper electrophoresis. Most of the acidic oligosaccharides were converted to neutral ones by sialidase digestion, indicating that they are sialyl derivatives. The neutral and sialidase-treated acidic oligosaccharides were fractionated by Bio-Gel P-4 column chromatography in combination with serial chromatography on immobilized lectin columns including a Wistaria floribunda agglutinin (WFA)-agarose column. WFA is known to bind oligosaccharides terminating with either an alpha- or beta-N-acetylgalactosamine residue. Structural studies of oligosaccharides in each fraction by sequential exoglycosidase digestion as well as methylation analysis revealed that CD36 contains high mannose-type, hybrid-type, and bi, tri-, and tetraantennary complex-type sugar chains. A portion of the hybrid-type and the complex-type sugar chains which bound to a WFA-agarose column (28% of all oligosaccharides) contained the GalNAc beta 1-->4GlcNAc group(s) instead of the Gal beta 1-->4GlcNAc group(s) in their outer chain moieties. Like oligosaccharides found in human luteinizing hormone [Weisshaar, G., Hiyama, J., Renwick, A. G., & Nimtz, M. (1991) Eur. J. Biochem. 195, 257-268], some of the GalNAc beta 1-->4GlcNAc groups found in the CD36 oligosaccharides were sialylated as the Neu5Ac alpha 2-->6GalNAc group. Furthermore, most of the hybrid-type sugar chains of CD36 with the Gal/GalNAc beta 1-->4GlcNAc beta 1-->2 outer chain on their Man alpha 1-->3 arm contained an unusual Man alpha 1-->2Man alpha 1-->3 group on their Man alpha 1-->6 arm.

Animals↗