© 1996 American Heart Association, Inc.
Articles |
Regulation of Monocyte CD36 and Thrombospondin-1 Expression by Soluble Mediators
the Department of Medicine (Hematology-Oncology) and the Program in Cell Biology and Genetics (H.Y.H.), Cornell University Medical College, New York, NY.
Correspondence to Dr Roy L. Silverstein, Division of Hematology-Oncology, Cornell University Medical College, 1300 York Ave, New York, NY 10021.
Abstract
CD36 is an 88-kD integral membrane protein expressed on platelets, monocytes, macrophages, certain microvascular endothelia, and retinal pigment epithelium. It functions as an adhesive receptor for thrombospondin-1 (TSP-1), collagen, and malaria-infected erythrocytes and as a scavenger receptor for oxidized LDL and photoreceptor outer segments. The CD36–TSP-1 interaction plays a role in cell adhesion and the phagocytosis of apoptotic cells by macrophages. Because of the potential importance of the CD36–TSP-1 interaction in mediating atherogenic and inflammatory processes, we studied their expression in human peripheral blood monocytes exposed to soluble mediators known to regulate inflammation and atherogenesis. RNase protection assays showed 6- to 12-fold increases in CD36 mRNA in response to interleukin-4, monocyte colony-stimulating factor, and phorbol myristate acetate, while lipopolysaccharide and dexamethasone strongly downregulated CD36 mRNA. The downregulation of CD36 mRNA was associated with the disappearance of surface expression of CD36 antigen and loss of TSP-1 surface-binding capacity. Upregulation of CD36 mRNA was associated with a modest increase in surface antigen expression and a larger expansion of an intracellular pool of CD36. As with CD36, monocytes treated with monocyte colony-stimulating factor showed a rapid increase in TSP-1 mRNA expression. Moreover, while dexamethasone treatment decreased CD36 expression, it resulted in a rapid increase in TSP-1 mRNA, and while PMA increased CD36 mRNA, it rapidly decreased TSP-1 expression. Interferon gamma, which had no effect on CD36 mRNA, rapidly increased steady-state TSP-1 mRNA. Thus, expression of both CD36 and its ligand TSP-1 is regulated by soluble mediators, although certain mediators induce concordant changes and others discordant changes.
Key Words: CD36 • thrombospondin-1 • scavenger receptor • cytokine • monocyte
Platelet glycoprotein IV, or CD36, is an 88-kD integral membrane glycoprotein expressed on platelets,1 monocytes and macrophages,2 3 and certain microvascular endothelia.4 CD36 functions as a receptor for the adhesive glycoproteins TSP-15 and collagen6 and for a ligand exposed on the surface of erythrocytes infected with the parasite Plasmodium falciparum.7 The CD36–TSP-1 interaction is involved in platelet-monocyte adhesion,3 8 platelet–tumor cell adhesion,9 platelet aggregation,10 macrophage uptake of apoptotic cells,11 12 and macrophage activation of latent TGF-ß13 and thus may play a critical role in initiating and regulating inflammation, atherogenesis, and tumor metastasis.14 Certain CD36 functions appear to be independent of adhesion and TSP-1 binding. For example, CD36 is the defining member of a novel family of "scavenger receptors" for modified lipoproteins15 16 17 and thus may contribute to the formation of foam cells in atherosclerotic plaque. Work from our laboratory, in fact, suggests that macrophage CD36 may account for as much as 70% of oxidized LDL uptake under certain "proatherogenic" conditions.18 We have also shown that CD36 participates in the binding and uptake of effete photoreceptors by retinal pigment epithelium.19 The ligand on the shed photoreceptors is not TSP-1 and may be modified lipid.
Regulation of CD36 function as a cellular receptor is complex. We have shown that melanoma cells and 3T3 fibroblasts transfected with the cDNA for human CD36 bind TSP-1 in a 1:1 stoichiometric ratio,9 whereas COS-7 cells similarly transfected do not bind TSP-1.1 In addition, although resting platelets express CD36, they do not bind TSP-1 with the same stoichiometry as activated platelets. Asch et al20 have shown that posttranslational phosphorylation and dephosphorylation of extracytoplasmic Ser/Thr residues on CD36 may regulate TSP-1 and collagen binding.
Because of the potential importance of monocyte/macrophage CD36 in atherogenic and inflammatory processes, we are studying the mechanisms by which expression of CD36 and its ligands are regulated. We have shown that "tethering" of PBMs on TNF-activated endothelium increases CD36 expression on the monocyte cell surface21 and that CD36 expression increases during in vitro differentiation of blood monocytes into macrophages.18 These regulatory events are presumably transcriptional in that steady-state mRNA levels increase concomitantly with protein, and upregulation is blocked with inhibitors of RNA synthesis.18 21 Expression of TSP-1, one of several CD36 ligands that has been studied in vascular smooth muscle, fibroblasts, and keratinocytes, is part of the early response to growth factors.22 TSP-1 gene expression in PBMs has not, however, been as thoroughly studied. We have shown that during monocyte differentiation into macrophages, TSP-1 expression disappears as CD36 expression increases.18
Sequence analysis of the 5' flanking region of the human CD36 gene reveals a number of consensus sequences for cis regulatory elements that suggest possible transcriptional regulation by soluble mediators, including glucocorticoids and cytokines.23 24 Since these soluble mediators play a critical role in atherogenesis and inflammation, we have studied the response of the CD36 and TSP-1 genes in human PBMs to mediators known to regulate monocyte inflammatory, atherogenic, and differentiation processes. We found that monocyte expression of both CD36 and TSP-1 was regulated by cytokines, glucocorticoids, and protein kinase C activators. Interestingly, while some agonists regulate receptor and ligand concordantly, others induce a discordant response, suggesting that certain monocyte CD36 functions, eg, oxidized LDL uptake, might require that CD36 remain unoccupied by other potential ligands such as TSP-1.
Methods
Materials
Murine monoclonal anti-CD36 IgG FA6 was obtained from the Vth International Workshop on Human Leukocyte Antigens,25 and 8A67 was from Dr J. Barnwell, New York University Medical Center, New York, NY. Monospecific rabbit anti-human platelet CD36 IgG was produced as previously described.26 Fluorescein-labeled goat anti-mouse IgG was from Kirkegaard & Perry, and horseradish peroxidase–conjugated goat anti-rabbit F(ab')2 and the ECL chemiluminescent peroxidase substrate kit for Western blots were obtained from Amersham. A full-length CD36 cDNA1 was obtained from Dr B. Seed, Massachusetts General Hospital, Boston, Mass. A 1.1-kb human TSP-1 cDNA27 subcloned into pGEM-2 was generously donated by Dr J. Lawler, Brigham and Women's Hospital, Boston, Mass, and a 1.1-kb human TSP-2 cDNA subcloned in pBluescript II was generously provided by Dr T. LaBell, University of Washington, Seattle. A human GAPDH cDNA clone was obtained from the American Type Culture Collection. Human recombinant granulocyte M-CSF, GM-CSF, IL-3, and IL-6 were generously provided by Genetics Institute. Human recombinant IFN-
and TNF-
were provided by Genentech. Human recombinant IL-4 was from Immunex. Restriction enzymes and actinomycin D were obtained from Boehringer Mannheim. RPMI 1640, versene, Dulbecco's PBS, fetal bovine serum, and the antibiotics gentamicin, penicillin, and streptomycin were obtained from GIBCO. Human AB serum, paraformaldehyde, PMA, dexamethasone, RNase A, RNase T1, and Escherichia coli LPS were purchased from Sigma Chemical Co. Sp6 RNA polymerase, T7 RNA polymerase, and plasmid pGEM-4Z were from Promega. The plasmid pBluescript KS was from Stratagene. Tissue-culture plates were obtained from Costar. Ficoll and Percoll for monocyte preparation were obtained from Pharmacia. All other reagents were of analytical grade.
Monocyte Isolation and Culture
Peripheral blood mononuclear cells were isolated from leukocyte-rich fractions diluted 1:1 with versene by using the Ficoll-Paque technique.21 28 The mononuclear fraction was washed in PBS and then resuspended in RPMI 1640 containing 0.05% gentamicin and supplemented with 5% heat-inactivated human AB serum. Aliquots of the cell suspension (5x106 mononuclear cells/mL) were allowed to adhere to wells of a 24-well tissue-culture plate at 37°C in a humidified 5% CO2 environment. After 30 minutes the wells were washed with PBS, and fresh medium was added to adherent cells. The cultured cells were then incubated with soluble mediators at saturable concentrations for various times at 37°C in a humidified 5% CO2 environment. In some experiments the mononuclear fraction from the Ficoll gradients was further separated by Percoll gradient centrifugation to obtain monocytes. These were then cultured in suspension in polytetrafluoroethylene-coated dishes. Monocyte purity as determined by using flow cytometry with a monoclonal antibody for CD14 was >90%, and viability was >98% as assessed by Trypan blue exclusion.
RNase Protection Assay
RNase protection assays were performed by using modifications of the methods of Thompson and Gillespie29 and Haines and Gillespie30 as described.18 21 The monocytes were washed and then lysed in 5 mol/L guanidine thiocyanate and 0.1 mol/L EDTA at 
2.5 to 5x106 cells/mL; hybridization was performed directly in 20-µL aliquots of cell lysate for 20 hours at 37°C with antisense 32P-labeled RNA probes. RNA probes were labeled to specific activities of 1 to 2x109 cpm/µg with [32P]UTP. CD36 riboprobes were generated18 21 by subcloning a 792-bp BamHI fragment from the 5' end of the CD36 cDNA into pBluescript KS. The resulting plasmid was linearized with EcoRI, and T7 RNA polymerase was used to transcribe an antisense probe of 792 bp. The protected fragment generated by this probe was 759 bp. The TSP-1 riboprobe was generated from the pGEM-2/TSP-1 plasmid linearized with HindIII and transcribed in vitro with Sp6 RNA polymerase to generate an antisense probe of 1275 bp. The protected fragment generated by this probe was 1200 bp.18 The GAPDH riboprobe was generated by subcloning a 744-bp Pst I–Xba I fragment from the 5'-most end of the cDNA into pGEM-4Z. The resulting plasmid was linearized with HindIII and transcribed in vitro with SP6 RNA polymerase to generate an antisense probe of 554 bp and a protected fragment of the same length. After overnight hybridization the samples were digested with RNase A and RNase T1, and the protected fragments were subjected to electrophoresis on 5% polyacrylamide gels in Tris-borate buffer. On all gels both radiolabeled probe and labeled probe incubated with the RNases were run as controls to verify that the protected fragments were of appropriate size and that the RNase digestion was adequate. Autoradiograms of the dry gels were assessed by densitometric scanning by using a UMAX UC630 flatbed scanner attached to a Macintosh IIci running National Institutes of Health Image software, and transcript levels were normalized to those obtained with the control GAPDH riboprobe. Scans were done in the linear range of response of the x-ray film as determined by scanning multiple exposures over varying periods of time.
Immunoblotting Analysis
Monocyte cultures were lysed in RIPA buffer (150 mmol/L NaCl, 1.0% NP-40, 0.5% deoxycholate, 0.1% SDS, and 50 mmol/L Tris, pH 7.4) and proteins (25 µg/lane) resolved through 8% SDS–polyacrylamide gel electrophoresis and then electrophoretically transferred to nitrocellulose paper. The nitrocellulose was then blocked for 2 hours in 20 mmol/L Tris, 150 mmol/L NaCl, and 0.05% Tween 20, pH 7.4 with 5% nonfat dry milk. The blocking solution was replaced with murine monoclonal anti-CD36 IgG FA6 (2 µg/mL) or specific rabbit anti-CD36 IgG (20 µg/mL) in the nitrocellulose blocking solution for 1 hour and washed with the same buffer three times for 10 min/time. Immunoreactive bands were detected after incubation with horseradish peroxide–conjugated goat secondary antibodies for 45 minutes followed by addition of ECL reagent and exposure to photographic film. In some experiments crude membrane fractions were obtained by lysing the cells in 1% NP-40 followed by sequential centrifugation at 3000g and 100 000g. In studies that compared intracellular versus cell-surface localization of CD36, cells were permeabilized by mild detergent lysis with 20 µg/mL digitonin followed by a low-speed spin (1500g) to isolate the cytosolic supernatant. The specificity of the separation procedure was verified through immunoblots to the membrane marker CD31.
Indirect Immunofluorescence Microscopy
Monocytes were seeded on coverslips placed in 24- or 12-well tissue-culture plates and incubated with soluble mediators or control medium for 16 hours at 37°C. The cells were then placed on ice for 10 minutes and washed in 4°C PBS for 15 minutes. To detect cell-surface CD36, cells were prepared by being fixed in 2% paraformaldehyde for 30 minutes on ice. To detect intracellular CD36, cells were permeabilized by fixation at -20°C in 100% methanol for 10 minutes. Cells were then washed twice (5 min/time) in 4°C PBS. The anti-CD36 murine monoclonal 8A6 was added to fixed cells for 30 minutes at 2 µg/mL. Cells were washed three times (10 min/time) in 4°C PBS, and fluorescein-labeled goat anti-mouse IgG (20 µg/mL) was added for 30 minutes. The coverslips were mounted on slides by using 15% polyvinyl alcohol and 65% glycerol in PBS, sealed in the dark, and photographed with a Nikon epifluorescence microscope equipped with Kodak Ektachrome ASA 400 slide film.
125I-TSP-1 Binding Studies
TSP-1 was purified from the releasate of thrombin-activated washed platelets by sequential heparin-affinity and anion-exchange chromatography and then labeled with Na125I by using immobilized chloramine T (IODOBEAD; Pierce Chemical Co).9 Binding of 125I-TSP-1 to purified PBMs was performed as described3 8 31 ; experiments were done at 0.1 µmol/L 125I-TSP-1. Nonspecific binding was determined as that not inhibited by EDTA or unlabeled TSP-1 and was generally <5% of input. CD36-dependent binding was defined as that inhibited by 2 µg/mL of the blocking murine monoclonal anti-CD36 IgG 8A6 and was >95% of specific binding.
Results
Freshly isolated adherent human monocytes were incubated with a panel of soluble mediators and analyzed for specific expression of CD36 mRNA by using a modified RNase protection assay. Treatment for 16 hours with M-CSF, IL-4, or PMA increased steady-state CD36 mRNA levels 6- to 12-fold compared with untreated control cells (Table
). In contrast, no change in CD36 mRNA was seen when PBMs were treated with TNF, IFN-, or IL-3, while a dramatic downregulation of CD36 mRNA was seen in response to LPS or dexamethasone. Time-course studies (Fig 1A) revealed that the increase in expression induced by M-CSF, IL-4, or PMA was apparent by 2 or 3 hours and persisted for at least 12 to 24 hours. Fig 1B shows a representative autoradiograph for M-CSF. In all cases the autoradiographs were quantified by using laser densitometry, and the amount of CD36-protected fragment was normalized to a control mRNA (GAPDH). No further increase in CD36 mRNA levels was seen if the cells were treated with cycloheximide along with the cytokines (not shown), demonstrating that the CD36 gene was not "superinducible." The increase was blocked, however, by the transcriptional inhibitor actinomycin D, demonstrating that the increase in steady-state levels of CD36 RNA was likely due to an increase in gene transcription. The downregulation of CD36 mRNA seen in response to LPS or dexamethasone was also rapid (Fig 2A), with loss of message apparent after 2 to 3 hours. By 12 hours, CD36 mRNA was not detectable. Fig 2B shows a representative autoradiograph for LPS. In all cases, a similar response to soluble mediators was seen with PBMs isolated by sequential Ficoll and Percoll density-gradient centrifugation and cultured in nonadherent polytetrafluoroethylene-coated dishes, demonstrating that adhesion to plastic was not necessary for the response.
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), 5 ng/mL IL-4 (
), 10-7 mol/L PMA (
), or medium alone (
) for varying times and then lysed in 5 mol/L guanidine thiocyanate. Aliquots were hybridized to 2x106 cpm of a 792-bp 32P-labeled CD36 antisense riboprobe and digested with RNase A and T1. Protected fragments were resolved by electrophoresis on 5% polyacrylamide gels, and autoradiograms of the dry gels were assessed by densitometric scanning that compared the 759-bp CD36 mRNA protected fragment with a GAPDH control. Fold change in density is expressed in arbitrary densitometric units. B, Representative autoradiograph showing CD36 and GAPDH protected fragments in cells treated with M-CSF.
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), 1 µg/mL LPS (•), or medium alone (
To correlate CD36 mRNA regulation with protein expression and function, we measured CD36 antigen levels in PBMs by indirect immunofluorescence microscopy, flow cytometry, and Western blotting and assessed CD36 function through 125I-TSP-1 binding. Indirect immunofluorescence flow cytometric analysis of cell-surface CD36 revealed only a slight shift in mean fluorescence intensity after exposure to soluble mediators. For example, after treatment with M-CSF, mean fluorescence intensity (measured as mean channel fluorescence) shifted from an average of 6.3 to an average of 7.1 (n=3; range of shift, 10% to 26%). To quantify functional CD36 surface expression, we also measured 125I-TSP-1 binding to these cells and found modest increases compared with untreated control cells. Fig 3 shows that specific CD36-dependent TSP-1 binding increased by 55±8% after exposure to IL-4 and 88±10% after exposure to M-CSF. Specific CD36-dependent binding was determined as that inhibited by 5 mmol/L EDTA or a 10-fold excess of unlabeled TSP-1 and by saturating concentrations of the CD36-blocking antibody 8A6.
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.05, **P
To rule out the possibility that the increase in CD36 mRNA was the result of either an alternatively spliced or prematurely terminated message producing a CD36 variant not recognizable by our anti-CD36 antibodies and that did not bind TSP-1, we also performed RNase protection assays by using riboprobes that spanned the entire length of the CD36 cDNA. We did not detect any protected fragments that did not correspond in size to protected fragments isolated from transfected cells that expressed a functional CD36 from a full-length CD36 cDNA (data not shown). Thus, all mRNA produced by the cytokine-treated monocytes was processed full length and was not alternatively spliced. We therefore next examined the possibility that soluble mediators might alter levels of intracellular CD36. Immunofluorescence microscopy of cells at times ranging from 4 to 48 hours of agonist exposure showed that while both the cell-surface and intracellular expression increased, an internal pool appeared to account for a large proportion of the increased CD36. Immunofluorescence microscopy on methanol-permeabilized cells showed a dramatic increase in intracellular CD36 in monocytes that had been exposed for 16 hours to M-CSF or IL-4 (Fig 4B, 4F, and 4G). Interestingly, pseudopodal extensions showed the highest levels of CD36 immunofluorescence (Fig 4G), with microvilli also exhibiting concentrated levels of CD36 (Fig 4F). Isotype-matched nonimmune murine IgG did not bind to PBMs, indicating specificity (Fig 4D and 4H). Efforts to colocalize the cytokine-induced intracellular pools of CD36 with known intracellular markers have not demonstrated CD36 accumulation in specific organelles.
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To estimate the relative change in total CD36 antigen and the proportion of intracellular versus surface CD36 expression, we performed densitometric scans of CD36 immunoblots. Blots of total cellular protein prepared from IL-4– and M-CSF–treated cells revealed an 8- to 10-fold increase compared with untreated cells (Fig 5, lanes 8 and 9 versus lane 7). This was thus similar to the increase seen in CD36 mRNA (Fig 1
). In contrast, CD36 antigen in the Triton X-100 insoluble fractions was increased by only twofold (Fig 5, lanes 2 and 3 versus lane 1). Blots were also performed on cells that were permeabilized by mild detergent lysis with 20 µg/mL digitonin to release intracellular contents. We found that M-CSF induced a more than sixfold increase in digitonin-released CD36 as well as modest increases in digitonin-insoluble pellets compared with nontreated cells.18 These results are consistent with the immunofluorescence microscopy data shown in Fig 4 and demonstrate that the intracellular pool of CD36 increased upon monocyte exposure to IL-4 and M-CSF.
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In contrast to the effects of IL-4 and M-CSF, the downregulation of CD36 mRNA by mediators such as LPS and dexamethasone was associated with a concomitant loss of CD36 surface expression as detected by immunofluorescence microscopy with the murine monoclonal anti-CD36 IgG FA6 (Fig 4C). The presence of monocytes in the wells was verified by phase-contrast microscopy and propidium iodide nuclear staining. Loss of expression was noticeable as early as 3 hours after incubation with LPS and was complete by 16 hours. In addition, total CD36 antigen as detected by Western blotting was also markedly decreased in LPS-treated (Fig 5, lane 4) and dexamethasone-treated (lane 6) compared with untreated (lane 1) cells. 125I-TSP-1 binding was measured to assess the functional status of surface CD36. TSP-1 binding was reduced by 85±6% after the monocytes were exposed for 16 hours to LPS and by 65±11% after they were exposed to dexamethasone (Fig 3).
Since PBMs have been reported to synthesize and secrete TSP-1, one of the physiological ligands for CD36, and since the TSP-1 gene is known to be regulated by soluble mediators in smooth muscle cells, keratinocytes, and fibroblasts,22 we also studied whether monocyte TSP-1 mRNA expression was regulated in a similar manner to CD36. As with CD36, monocytes treated with M-CSF showed a rapid increase in TSP-1 mRNA expression (Fig 6). In contrast, while dexamethasone treatment decreased CD36 expression, it resulted in an increase in TSP-1 mRNA; and while PMA increased CD36 mRNA, it decreased TSP-1 expression. IFN-, which had no effect on CD36 mRNA, rapidly increased TSP-1 expression. Thus, regulation of the receptor (CD36) and one of its ligands (TSP-1) can be dissociated by certain soluble mediators (Table). We also examined TSP-2 mRNA expression in these cells and found that TSP-2 was not expressed in PBMs and was not induced by exposure to cytokines (data not shown).
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Discussion
CD36 is a multifunctional receptor that may play important roles in monocyte/macrophage biology, eg, in mediating phagocytosis of apoptotic cells,11 12 activation of latent TGF-ß,13 and uptake of oxidized LDL.15 16 Recent evidence, in fact, has implicated CD36 as a major macrophage scavenger receptor for oxidized LDL18 32 and thus an important participant in the generation of atheroma. Modulation of monocyte/macrophage CD36 expression may therefore be an important aspect of the response to inflammatory and proatherogenic mediators and may have potential use in a pharmacological approach to treating inflammation and atherosclerosis. By using freshly isolated human monocytes and a modified RNase protection assay to quantify steady-state mRNA levels and immunofluorescence microscopy, immunoblotting, and 125I-TSP-1 binding assays to assess protein expression and function, we now report the first demonstration that monocyte expression of CD36 is regulated by soluble mediators. We also assessed whether TSP-1, a ligand for CD36 that is synthesized and secreted by monocytes, was regulated in a similar manner by the same soluble mediators. We found that CD36 expression could be both upregulated and downregulated by soluble mediators. For example, LPS and glucocorticoids rapidly and dramatically downregulated CD36 steady-state mRNA levels. This was associated with the disappearance of CD36 surface expression and loss of TSP-1 surface-binding capacity. Such loss of cell-surface CD36 expression may have important in vivo consequences; eg, by limiting the local generation of active TGF-ß, the inflammatory response could be dulled. Foam cell formation in atheromatous lesions might also be limited by downregulation of CD36. Interestingly, expression of the type I/II macrophage scavenger receptor is also downregulated by LPS,33 suggesting that regulation of monocyte/macrophage scavenger receptors may in some cases be concordant.
Certain agonists, including IL-4, M-CSF, and the protein kinase C activator PMA, induced an 8- to 12-fold increase in CD36 mRNA and protein levels. M-CSF is of particular interest because some data show accumulation of this cytokine in atheromatous lesions.34 Induction of CD36 by these mediators was rapid and persisted for at least 24 hours. While cell-surface expression of CD36 was only modestly increased (less than twofold), a much more dramatic increase in intracellular antigen was seen. The identity and function of this intracellular pool of CD36 is not clear. Coimmunolocalization studies with intracellular markers have not shown specific localization to a known intracellular membrane compartment (H.Y.H. and R.L.S., unpublished data, 1995). The intracellular pool may represent translated CD36 awaiting transport to the plasma membrane; ie, increased CD36 expression might be regulated at several stages, including a posttranslation level of control. This is consistent with other monocyte responses in that it has long been recognized that mononuclear phagocytes must be "primed" to perform some of their critical physiological functions, such as the killing of microbial pathogens and scavenging for senescent cells.35 Signals responsible for priming generally differ from those that subsequently activate effector functions. Eierman et al36 have shown that adhesion to immobilized substrates primes monocytes by inducing expression of TNF and M-CSF mRNA. A second signal such as LPS is then required to induce expression and secretion of the proteins. Thus, one interpretation of our data is that M-CSF and IL-4 prime the monocytes to upregulate the intracellular levels of CD36 but that translocation of the protein to the cell surface may require a second signal. IFN- and LPS, which are known activators of mononuclear phagocytes, did not, however, induce increased surface expression of CD36 on cells primed with IL-4 or M-CSF. This was not unexpected since we have shown that these agonists downregulate CD36 mRNA. Other agonists may therefore play this role. We have shown induction of CD36 surface expression on PBMs upon adhesion to TNF-activated endothelium.21 This phenomenon appears to be mediated through monocyte engagement with endothelial cell–surface E-selectin and occurs primarily at the transcriptional level.21 It is thus possible that diverse external stimuli including soluble mediators and specific adhesion molecules may function in concert to regulate CD36 expression.
Alternatively, it is possible that the intracellular pool represents CD36 that has been initially targeted to the plasma membrane and subsequently returned cytoplasmically as a component of receptor cycling; such an action might occur during phagocytosis of senescent cells or uptake of oxidized LDL. Similar behavior has been reported for other monocyte/macrophage receptors, including the LDL receptor.37 CD36-dependent uptake of oxidized LDL by human culture-derived macrophages exposed to M-CSF is dramatically increased compared with untreated cells despite only a modest increase in steady-state surface CD36 expression.18 This is consistent with at least some component of active receptor cycling.
Monocyte expression of the CD36 ligand TSP-1 was not regulated in a similar manner to CD36. Some agonists, such as GM-CSF and M-CSF, induced rapid upregulation of both TSP-1 and CD36 mRNA. In contrast, while dexamethasone treatment decreased CD36 expression, it resulted in a rapid increase in TSP-1 mRNA; and while PMA increased CD36 mRNA, it rapidly decreased TSP-1 expression. IFN-, which had no effect on CD36 mRNA, increased TSP-1 mRNA. Thus, while both CD36 and its ligand are regulated by soluble mediators, certain mediators induce concordant changes and others elicit discordant responses. The opposite effects exhibited by the same agonist on CD36 and TSP-1 suggest that certain monocyte functions require that TSP-1 not compete for unoccupied sites on CD36. It is of interest that CD36-dependent phagocytosis of senescent human neutrophils is inhibited in vitro by soluble TSP-1.11 IL-4, which has been postulated to be an "anti-inflammatory" cytokine38 by virtue of its ability to downregulate production of proinflammatory cytokines such as IL-1 and TNF, upregulated CD36 mRNA and downregulated TSP-1 mRNA in our system. IL-4 has also been reported to upregulate vß3, which functions with CD36 on macrophages as a coreceptor for senescent leukocytes.39 Thus, monocyte/macrophage capacity to clear senescent cells and thus limit tissue damage at sites of inflammation would be increased by this anti-inflammatory cytokine.
Selected Abbreviations and Acronyms
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Acknowledgments
This work was supported in part by National Institutes of Health (NIH) grants HL 42540, HL 18828 (NIH Specialized Center of Research in Thrombosis), and HL 46403 (NIH Program Project in Vascular Cell Signalling) to Dr Silverstein. We thank Qinghu Zheng for his technical assistance.
Received August 9, 1995; revision received March 12, 1996; References
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