Transforming Growth Factor-β1 (TGF-β1) and TGF-β2 Decrease Expression of CD36, the Type B Scavenger Receptor, through Mitogen-activated Protein Kinase Phosphorylation of Peroxisome Proliferator-activated Receptor-γ

Abstract

CD36, the macrophage type B scavenger receptor, binds and internalizes oxidized low density lipoprotein, a key event in the development of macrophage foam cells within atherosclerotic lesions. Expression of CD36 in monocyte/macrophages is dependent on differentiation status and exposure to soluble mediators. In this study, we investigated the effect of transforming growth factor-β1 (TGF-β1) and TGF-β2 on the expression of CD36 in macrophages. Treatment of phorbol ester-differentiated THP-1 macrophages with TGF-β1 or TGF-β2 significantly decreased expression of CD36 mRNA and surface protein. TGF-β1/TGF-β2 also inhibited CD36 mRNA expression induced by oxidized low density lipoprotein and 15-deoxyΔ12,14 prostaglandin J2, a peroxisome proliferator-activated receptor (PPAR)-γ ligand, suggesting that the TGF-β1/TGF-β2 down-regulated CD36 expression by inactivating PPAR-γ-mediated signaling. TGF-β1/TGF-β2 increased phosphorylation of both mitogen-activated protein (MAP) kinase and PPAR-γ, whereas MAP kinase inhibitors reversed suppression of CD36 and inhibited PPAR-γ phosphorylation induced by TGF-β1/TGF-β2. Finally, MAP kinase inhibitors alone increased expression of CD36 mRNA and surface protein but had no effect on PPAR-γ protein levels. Our data demonstrate for the first time that TGF-β1 and TGF-β2 decrease expression of CD36 by a mechanism involving phosphorylation of MAP kinase, subsequent MAP kinase phosphorylation of PPAR-γ, and a decrease in CD36 gene transcription by phosphorylated PPAR-γ. CD36, the macrophage type B scavenger receptor, binds and internalizes oxidized low density lipoprotein, a key event in the development of macrophage foam cells within atherosclerotic lesions. Expression of CD36 in monocyte/macrophages is dependent on differentiation status and exposure to soluble mediators. In this study, we investigated the effect of transforming growth factor-β1 (TGF-β1) and TGF-β2 on the expression of CD36 in macrophages. Treatment of phorbol ester-differentiated THP-1 macrophages with TGF-β1 or TGF-β2 significantly decreased expression of CD36 mRNA and surface protein. TGF-β1/TGF-β2 also inhibited CD36 mRNA expression induced by oxidized low density lipoprotein and 15-deoxyΔ12,14 prostaglandin J2, a peroxisome proliferator-activated receptor (PPAR)-γ ligand, suggesting that the TGF-β1/TGF-β2 down-regulated CD36 expression by inactivating PPAR-γ-mediated signaling. TGF-β1/TGF-β2 increased phosphorylation of both mitogen-activated protein (MAP) kinase and PPAR-γ, whereas MAP kinase inhibitors reversed suppression of CD36 and inhibited PPAR-γ phosphorylation induced by TGF-β1/TGF-β2. Finally, MAP kinase inhibitors alone increased expression of CD36 mRNA and surface protein but had no effect on PPAR-γ protein levels. Our data demonstrate for the first time that TGF-β1 and TGF-β2 decrease expression of CD36 by a mechanism involving phosphorylation of MAP kinase, subsequent MAP kinase phosphorylation of PPAR-γ, and a decrease in CD36 gene transcription by phosphorylated PPAR-γ. oxidized low density lipoprotein 15-deoxyΔ12,14prostaglandin J2 fluorescence-activated cell sorting glyceraldehyde-3-phosphate dehydrogenase mitogen-activated protein phosphate-buffered saline phorbol 12-myristate 13-acetate peroxisome proliferator-activated receptor transforming growth factor Macrophage scavenger receptors play a significant role in atherosclerotic foam cell development because of their ability to bind and internalize OxLDL1(1.Steinberg D. Circulation. 1987; 76: 508-514Crossref PubMed Scopus (119) Google Scholar, 2.Steinberg D. Parthasarathy S. Carew T. Khoo J. Witztum J. N. Engl. J. Med. 1989; 320: 915-919Crossref PubMed Google Scholar, 3.Gown A. Tsukada T. Ross R. Am. J. 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Cell. 1998; 93: 241-252Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar, 23.Nagy L. Tontonoz P. Alvarez J. Chen H. Evans R. Cell. 1998; 93: 229-240Abstract Full Text Full Text PDF PubMed Scopus (1594) Google Scholar). PPAR-γ is a member of a nuclear hormone superfamily that can heterodimerize with the retinoid X receptor and act as a transcriptional regulator of genes encoding proteins involved in adipogenesis and lipid metabolism (24.Tontonoz P. Hu E. Spiegelman B. Curr. Opin. 2t. Dev. 1995; 5: 571-576Crossref PubMed Scopus (404) Google Scholar). Phorbol esters (phorbol 12-myristate 13-acetate (PMA) in particular), macrophage-colony-stimulating factor and interleukin-4 have also been shown to increase monocyte/macrophage expression of CD36 (25.Yesner L. Huh H. Pearce S.F.A. Silverstein R. Arterioscler. Thromb. 1996; 16: 1019-1025Crossref Scopus (151) Google Scholar), whereas expression of CD36 is down-regulated in response to cholesterol efflux (26.Han J. 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Transforming growth factor-β1 (TGF-β1) and TGF-β2 are multifunctional mediators that regulate cellular growth, migration, adhesion, extracellular matrix formation, and apoptosis (28.Sporn M. Roberts A. Wakefield L. Crombrugghe B. J. Cell Biol. 1987; 105: 1039-1045Crossref PubMed Scopus (1010) Google Scholar). Smads, a novel family of signaling proteins, are the primary downstream signaling mediators activated following TGF-β receptor ligation (29.Engel M.E. Datta P.K. Moses H.L. J. Cell. Biochem. 1998; 30–31: 111-122Crossref Google Scholar). Heteromeric Smad complexes translocate into the nucleus and act as transcription factors for TGF-β-responsive genes (30.Massague J. Annu. Rev. Biochem. 1998; 67: 753-791Crossref PubMed Scopus (3985) Google Scholar). However, in addition to Smad proteins, MAP kinases have also been implicated in mediating downstream TGF-β signaling (31.Chin B.Y. Petrache I. Choi A.M.K. Choi M.E. J. Biol. Chem. 1999; 274: 11362-11368Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 32.Yamaguchi K. Shirakabe K. Shibuya H. Irie K. Oishi I. Ueno N. Taniguchi T. Nishida E. Matsumoto K. Science. 1995; 270: 2008-2011Crossref PubMed Scopus (1175) Google Scholar, 33.Hartsough M.T. Frey R.S. Zipfel P.A. Buard A. Cook S.J. McCormick F. Mulder K.M. J. Biol. Chem. 1996; 271: 22368-22375Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 34.Atfi A. Buisine M. Mazars A. Gespach C. J. Biol. Chem. 1997; 272: 24731-27734Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar). We evaluated the signaling mechanisms involved in the inhibition of CD36 by TGF-β1 and TGF-β2. We demonstrate that TGF-β1 and TGF-β2 decrease expression of CD36 by a mechanism involving phosphorylation of MAP kinase, subsequent MAP kinase phosphorylation of PPAR-γ, and a decrease in CD36 gene transcription by phosphorylated PPAR-γ. THP-1 cells, a human monocytic cell line, were obtained from ATCC (Manassas, VA). They were cultured in RPMI 1640 medium containing 10% fetal calf serum, 50 μg/ml each of penicillin and streptomycin, and 2 mm glutamine. Cells were adjusted to a density of 2.5 × 105cells/cm2 in 100-mm dishes and treated with 200 nm PMA to induce the differentiation of THP-1 monocytes into macrophages. After 8 h of treatment, PMA was removed and cells were washed twice with phosphate-buffered saline (PBS). Incubation was continued overnight in complete medium before initiation of experiments. TGF-β1 and TGF-β2 were purchased from R & D Systems (Minneapolis, MN). PMA and 15d-PGJ2 were obtained from Calbiochem (San Diego, CA). Cells were lysed in RNAzolTM B (Tel-Test, Inc., Friendswood, TX), chloroform was extracted, and total cellular RNA was precipitated in isopropanol. After washing with 80 and 100% ethanol, the dried pellet of total RNA was dissolved in distilled water and quantified by UV spectroscopy. Poly(A+) RNA was purified from approximately 100 μg of total RNA using the Poly(A)Ttract® mRNA isolation system III (Promega, Madison, WI). Poly(A+) RNA was loaded on 1% formaldehyde agarose gels. Following electrophoresis RNA was transferred to a Zeta-probe® GT genomic tested blotting membrane (Bio-Rad) in 10× SSC by capillary force overnight. The blot was UV cross-linked for 2 min and then prehybridized with HybrisolTM (Oncor, Inc., Gaithersburg, MD) for 30 min before the addition of 32P-randomly primed probes for CD36 or GAPDH. After overnight hybridization, membranes were washed twice for 20 min each time with 2× SSC and 0.2% SDS, and twice for 20 min each time with 0.2× SSC and 0.2% SDS at 55 °C. The blot was autoradiographed by exposure to a x-ray film (X-OmatTMAR, Eastman Kodak Co.). Semiquantitative analysis of autoradiograms was assessed by densitometric scanning using a UMAX (Santa Clara, CA) UC630 flatbed scanner attached to a Macintosh IIci (Apple Computer, Inc., Cupertino, CA) running National Institutes of Health Image software (Bethesda, MD). The probe for CD36 was generated by reverse transcription-polymerase chain reaction. The sequences of 5′- and 3′-oligonucleotides used were ATGGGCTGTGACCGGAACT (285–304) and ACAGACCAACTGTGGTAG (871–889), respectively. After treatment, cells were suspended by the addition of trypsin and washed three times with PBS. Approximately 2 × 106 cell were suspended in 300 μl of PBS containing 5% mouse serum and incubated for 30 min at room temperature while shaking. Cells then were incubated with 10 μl of mouse anti-human CD36 conjugated to fluorescine isothiocyanate isomer 1 (Chemicon International Inc., CA). After incubation for 2 h with antibody at room temperature, cells were washed three times with PBS. After suspension in PBS, the cells analyzed by flow with a In addition, were of cells on using a were washed twice with PBS and then and lysed in mm mm 1% 1% 1 mm 50 mm 1 mm 50 μg/ml and 50 μg/ml The was for min at and the was transferred to a After of protein by of were loaded on electrophoresis and transferred membrane The membrane was with a of containing 5% for 2 was incubated with MAP kinase or PPAR-γ (Santa CA) for 2 h at room temperature, by washing three times for 10 min each with The blot was with containing 5% by incubation with for 1 h at room After washing three times for 10 min each with the membrane was incubated for 1 min in a of of blot 1 and The membrane was then to film before THP-1 macrophages in dishes were incubated with Following treatment, cells were washed three times with PBS and then lysed in 200 μl of were from each were incubated with anti-human PPAR-γ for 1 h at °C. was and incubation was continued overnight at °C. After washing three times with PBS, the was to and for min before on a electrophoresis After the was dried and to induce to macrophage THP-1 cells were treated with PMA After of treatment, cells and not removed by PMA was removed by washing with PBS, and the cells were incubated overnight in complete the effect of TGF-β1 and TGF-β2 on expression of CD36 THP-1 cells were treated with of TGF-β1 or TGF-β2 for TGF-β1 significantly decreased CD36 mRNA expression at a broad of in a with inhibition at In TGF-β2 decreased CD36 mRNA expression at and in a A time that both TGF-β1 and TGF-β2 decreased CD36 mRNA expression by the of decrease was with of CD36 mRNA expression in response to and THP-1 macrophages were treated with TGF-β or TGF-β2 in complete medium for the Expression of CD36 mRNA was analyzed as in Image the decrease in CD36 mRNA in response to TGF-β1 and TGF-β2 was with decreased cell surface expression of CD36 we evaluated the CD36 surface expression by fluorescence-activated cell sorting and using CD36 surface expression in THP-1 cells was to PMA differentiation but increased significantly following PMA with the decrease of CD36 mRNA expression in the of THP-1 cells with TGF-β1 or TGF-β2 CD36 surface the mechanism(s) by which TGF-β1 and TGF-β2 decreased CD36 THP-1 cells were treated with OxLDL or 15d-PGJ2 in the and of TGF-β1 or TGF-β2. OxLDL and 15d-PGJ2 PPAR-γ and increase transcription of genes (22.Tontonoz P. Nagy L. Alvarez J. Thomazy V. Evans R. Cell. 1998; 93: 241-252Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar, 23.Nagy L. Tontonoz P. Alvarez J. Chen H. Evans R. Cell. 1998; 93: 229-240Abstract Full Text Full Text PDF PubMed Scopus (1594) Google Scholar). both OxLDL and 15d-PGJ2 increased CD36 mRNA expression induction was significantly by both TGF-β1 and TGF-β2 suggesting that TGF-β1 and TGF-β2 PPAR-γ-mediated transcriptional activation of of induction of CD36 mRNA expression in response to PPAR-γ activation that TGF-β1 and TGF-β2 PPAR-γ transcriptional PPAR-γ MAP kinase phosphorylation sequences M. D. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar) and because MAP phosphorylation of PPAR-γ had been shown to PPAR-γ transcriptional M. D. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar), we evaluated the effect of TGF-β1 or TGF-β2 on MAP kinase and macrophages were treated with TGF-β1 or both the and of MAP kinase were and with induction of phosphorylation a the addition of TGF-β1 or TGF-β2 We evaluated the phosphorylation status of PPAR-γ in response to TGF-β1 and TGF-β2. THP-1 macrophages were treated with TGF-β1 and TGF-β2 for 10 h to analysis for both PPAR-γ and blot analysis that was in but with TGF-β1 or TGF-β2 induced expression of In addition, THP-1 macrophages were incubated with by with TGF-β2 or the MAP kinase inhibitors and for 10 PPAR-γ was increased in cells and in cells to cells In two MAP kinase and significantly PPAR-γ phosphorylation TGF-β2 and MAP kinase inhibitors had no effect on PPAR-γ protein levels A TGF-β and MAP kinase inhibitors on PPAR-γ that MAP kinase inhibitors induce expression of CD36 in macrophages. macrophages were treated with two MAP kinase and MAP kinase inhibitors significantly increased CD36 mRNA analysis with the increase of CD36 mRNA expression by MAP kinase surface protein of CD36 was also increased Finally, we evaluated the of MAP kinase inhibitors on CD36 expression in the of TGF-β1 and TGF-β2. Macrophage with TGF-β1 or TGF-β2 decreased expression of CD36 mRNA MAP kinase inhibitors increased expression of CD36 mRNA and also the inhibition of CD36 mRNA in response to TGF-β1 or TGF-β2 Our data demonstrate that TGF-β1 and TGF-β2 expression of CD36 by phosphorylation of the and of MAP kinase, which in in MAP phosphorylation of PPAR-γ. of PPAR-γ in decreased CD36 gene MAP kinase inhibitors alone increase expression of CD36 by and PPAR-γ. data the of regulation of PPAR-γ-mediated gene expression and demonstrate are to the transcriptional of PPAR-γ and CD36 gene to (24.Tontonoz P. Hu E. Spiegelman B. Curr. Opin. 2t. Dev. 1995; 5: 571-576Crossref PubMed Scopus (404) Google Scholar). The three and in their bind to and are activated by diverse as chain and Tontonoz P. Chen J. Spiegelman Evans Cell. 1995; Full Text PDF PubMed Scopus Google Scholar), and the class of J.M. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). as growth factor and growth factor, have been shown to PPAR-γ the MAP kinase signaling and to decrease PPAR-γ transcriptional J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). The of PPAR-γ a MAP kinase in a and M. D. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). PPAR-γ proteins on as a of phosphorylation A. M. A. Hu E. Spiegelman B. J. Clin. Invest. 1996; PubMed Scopus Google A. Mol. Cell. Biol. 1996; 16: PubMed Google Scholar). A MAP kinase is phosphorylated by extracellular kinase 2 and kinase M. D. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). significantly both and transcriptional activation by PPAR-γ. M. D. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). is by MAP kinase phosphorylation of on J. Biol. 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A. 1992; PubMed Scopus Google Scholar). of the receptor and retinoid X receptor modulates of the receptors and P. A. C. P. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). In addition, the MAP phosphorylation of on the receptor transcriptional activation by the S. H. Y. T. S. H. S. Y. Nishida E. H. Science. 1995; 270: PubMed Scopus Google Scholar). in phosphorylation of nuclear receptors their transcriptional MAP kinase phosphorylation of PPAR-γ its are the primary downstream signaling mediators activated following TGF-β receptor ligation (29.Engel M.E. Datta P.K. Moses H.L. J. Cell. Biochem. 1998; 30–31: 111-122Crossref Google Scholar, J. Annu. Rev. Biochem. 1998; 67: 753-791Crossref PubMed Scopus (3985) Google Scholar), MAP kinases have also been to downstream signaling (31.Chin B.Y. Petrache I. Choi A.M.K. Choi M.E. J. Biol. Chem. 1999; 274: 11362-11368Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 32.Yamaguchi K. Shirakabe K. Shibuya H. Irie K. Oishi I. Ueno N. Taniguchi T. Nishida E. Matsumoto K. Science. 1995; 270: 2008-2011Crossref PubMed Scopus (1175) Google Scholar, 33.Hartsough M.T. Frey R.S. Zipfel P.A. Buard A. Cook S.J. McCormick F. Mulder K.M. J. Biol. Chem. 1996; 271: 22368-22375Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 34.Atfi A. Buisine M. Mazars A. Gespach C. J. Biol. Chem. 1997; 272: 24731-27734Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar). Our data MAP phosphorylation of PPAR-γ in expression of CD36 in response to TGF-β and demonstrate that MAP kinase inhibitors expression of However, we the that other downstream signaling by TGF-β activation of MAP kinase can also regulate CD36 In we for the first time that a growth factor expressed within atherosclerotic phosphorylation of PPAR-γ, its transcriptional and expression of the type B scavenger receptor, TGF-β and PPAR-γ are expressed by monocyte/macrophages (22.Tontonoz P. Nagy L. Alvarez J. Thomazy V. Evans R. Cell. 1998; 93: 241-252Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar, M. A. T. C. C. 1998; PubMed Scopus Google Scholar), and PPAR-γ been in foam cells within atherosclerotic (22.Tontonoz P. Nagy L. Alvarez J. Thomazy V. Evans R. Cell. 1998; 93: 241-252Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar), its of expression is with the of M. J. L. A. J. J. Witztum J. J. W. C. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). data may have to both atherosclerotic foam cell by CD36 as as expression of other mediators expressed within lesions.