Oxysterol Activators of Liver X Receptor and 9-cis-Retinoic Acid Promote Sequential Steps in the Synthesis and Secretion of Tumor Necrosis Factor-α from Human Monocytes

Liver X receptor α (LXRα), is a nuclear hormone receptor that is activated by oxysterols and plays a crucial role in regulating cholesterol and lipid metabolism in liver and cholesterol efflux from lipid-loaded macrophages. Here we show that treatment of human peripheral blood monocytes or monocytic THP-1 cells with the LXR ligand 22(R)-hydroxycholesterol (22(R)-HC), in combination with 9-cis-retinoic acid (9cRA), a ligand for the LXR heterodimerization partner retinoid X receptor (RXR), results in the specific induction of the potent pro-apoptotic and pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). Promoter analysis, inhibitor studies, and order-of-addition experiments demonstrated that TNF-α induction by 22(R)-HC and 9cRA occurs by a novel two-step process. The initial step involves 22(R)-HC-dependent induction of TNF-α mRNA, and intracellular accumulation of TNF-α protein, mediated by binding of LXRα/RXRα to an LXR response element at position −879 of the TNF-α promoter. Subsequent cell release of TNF-α protein occurs via a separable 9cRA-dependent, LXRα-independent step that requires de novo transcription and protein synthesis. Our findings reveal a potentially new dimension of the physiological role of LXRα and identify a unique multistep pathway of TNF-α production that may be of consequence to the normal function of LXR in monocyte/macrophages and in disease conditions such as atherosclerosis. Liver X receptor α (LXRα), is a nuclear hormone receptor that is activated by oxysterols and plays a crucial role in regulating cholesterol and lipid metabolism in liver and cholesterol efflux from lipid-loaded macrophages. Here we show that treatment of human peripheral blood monocytes or monocytic THP-1 cells with the LXR ligand 22(R)-hydroxycholesterol (22(R)-HC), in combination with 9-cis-retinoic acid (9cRA), a ligand for the LXR heterodimerization partner retinoid X receptor (RXR), results in the specific induction of the potent pro-apoptotic and pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). Promoter analysis, inhibitor studies, and order-of-addition experiments demonstrated that TNF-α induction by 22(R)-HC and 9cRA occurs by a novel two-step process. The initial step involves 22(R)-HC-dependent induction of TNF-α mRNA, and intracellular accumulation of TNF-α protein, mediated by binding of LXRα/RXRα to an LXR response element at position −879 of the TNF-α promoter. Subsequent cell release of TNF-α protein occurs via a separable 9cRA-dependent, LXRα-independent step that requires de novo transcription and protein synthesis. Our findings reveal a potentially new dimension of the physiological role of LXRα and identify a unique multistep pathway of TNF-α production that may be of consequence to the normal function of LXR in monocyte/macrophages and in disease conditions such as atherosclerosis. Liver X receptors (LXRα (NR1H3) and LXRβ (NR1H2)) 1The abbreviations used are:LXRliver X receptor22(R)-HC22(R)-hydroxycholesterol22(S)-HC22(S)-hydroxycholesterol9cRA9-cis-retinoic acidLXRELXR-response elementoxLDLoxidized low density lipoproteinRXR9-cis-retinoic acid receptor (retinoid X receptor)TNF-αtumor necrosis factor-αILinterleukinLPSlipopolysaccharideCMVcytomegalovirusELISAenzyme-linked immunosorbent assayApoEapolipoprotein EMTVmurine mammary tumor virus 1The abbreviations used are:LXRliver X receptor22(R)-HC22(R)-hydroxycholesterol22(S)-HC22(S)-hydroxycholesterol9cRA9-cis-retinoic acidLXRELXR-response elementoxLDLoxidized low density lipoproteinRXR9-cis-retinoic acid receptor (retinoid X receptor)TNF-αtumor necrosis factor-αILinterleukinLPSlipopolysaccharideCMVcytomegalovirusELISAenzyme-linked immunosorbent assayApoEapolipoprotein EMTVmurine mammary tumor virus are recently described members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are important in the regulation of genes that govern cholesterol homeostasis in the liver and cholesterol efflux from peripheral tissues. LXRs are bound by and activated by specific cholesterol metabolites, including oxysterols, and regulate the expression of target genes by binding to specific promoter response elements (LXREs) in association with the obligate heterodimerization partner, retinoid X receptor (RXR), the receptor for 9-cis-retinoic acid (9cRA) (1Repa J.J. Mangelsdorf D.J. Annu. Rev. Cell Dev. Biol. 2000; 16: 459-481Crossref PubMed Scopus (598) Google Scholar). Natural ligands for LXR include 22(R)-hydroxycholesterol (22(R)-HC), 24(S),25-epoxycholesterol, and 25-hydroxycholesterol (2Janowski B.A. Willy P.J. Devi T.R. Falck J.R. Mangelsdorf D.J. Nature. 1996; 383: 728-731Crossref PubMed Scopus (1440) Google Scholar, 3Lehmann J.M. Kliewer S.A. Moore L.B. Smith-Oliver T.A. Oliver B.B., Su, J.L. Sundseth S.S. Winegar D.A. Blanchard D.E. Spencer T.A. Willson T.M. J. Biol. Chem. 1997; 272: 3137-3140Abstract Full Text Full Text PDF PubMed Scopus (1028) Google Scholar, 4Janowski B.A. Grogan M.J. Jones S.A. Wisely G.B. Kliewer S.A. Corey E.J. Mangelsdorf D.J. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 266-271Crossref PubMed Scopus (780) Google Scholar), compounds that have been found free in serum and in association with atherogenic oxidized low density lipoprotein (oxLDL) particles (5Dixon R. Furutachi T. Lieberman S. Biochem. Biophys. Res. Commun. 1970; 40: 161-165Crossref PubMed Scopus (30) Google Scholar, 6Brown A.J. Dean R.T. Jessup W. J. Lipid Res. 1996; 37: 320-335Abstract Full Text PDF PubMed Google Scholar, 7Kandutsch A.A. Chen H.W. Heiniger H.J. Science. 1978; 201: 498-501Crossref PubMed Scopus (403) Google Scholar). In the liver, LXRα serves as a sterol sensor and regulates the expression of genes that influence cholesterol metabolism and homeostasis, including the genes encoding cholesterol 7α-hydroxylase, which controls the cholesterol/bile acid synthetic pathway, and sterol regulatory element-binding protein-1c, a key transcription factor that regulates expression of genes important in fatty acid biosynthesis (6Brown A.J. Dean R.T. Jessup W. J. Lipid Res. 1996; 37: 320-335Abstract Full Text PDF PubMed Google Scholar,8Willy P.J. Umesono K. Ong E.S. Evans R.M. Heyman R.A. Mangelsdorf D.J. Genes Dev. 1995; 9: 1033-1045Crossref PubMed Scopus (908) Google Scholar, 9Peet D.J. Turley S.D., Ma, W. Janowski B.A. Lobaccaro J.M. Hammer R.E. Mangelsdorf D.J. Cell. 1998; 93: 693-704Abstract Full Text Full Text PDF PubMed Scopus (1230) Google Scholar, 10Schultz J.R., Tu, H. Luk A. Repa J.J. Medina J.C., Li, L. Schwendner S. Wang S. Thoolen M. Mangelsdorf D.J. Lustig K.D. Shan B. Genes Dev. 2000; 14: 2831-2838Crossref PubMed Scopus (1380) Google Scholar, 11Repa J.J. Liang G., Ou, J. Bashmakov Lobaccaro J.M. Shan B. J.L. Mangelsdorf D.J. Genes Dev. 2000; 14: PubMed Scopus Google Scholar). have that LXRα is for normal cholesterol homeostasis and of cholesterol in D.J. Turley S.D., Ma, W. Janowski B.A. Lobaccaro J.M. Hammer R.E. Mangelsdorf D.J. Cell. 1998; 93: 693-704Abstract Full Text Full Text PDF PubMed Scopus (1230) Google that LXRα plays a role in by regulating cholesterol efflux from lipid-loaded is by induction of genes encoding the and which cholesterol that and free cholesterol efflux from monocytes and lipid-loaded Wang J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, K. R.M. Biochem. Biophys. Res. Commun. 2000; PubMed Scopus Google Scholar, A. Repa J.J. Lobaccaro J.M. A. Mangelsdorf D.J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, A. B.A. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar). cholesterol is to density and to the liver is to and (1Repa J.J. Mangelsdorf D.J. Annu. Rev. Cell Dev. Biol. 2000; 16: 459-481Crossref PubMed Scopus (598) Google Scholar). The key role of LXR as a in the cholesterol efflux and intracellular cholesterol is by the findings that the genes encoding which is for density lipoprotein is a target of LXR B.A. Repa J.J. Mangelsdorf D.J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The role of LXRα in regulating cholesterol in is of disease lipid accumulation in the of is of to the and of and and particles in that have the lipid-loaded cells that the fatty of A.J. Nature. 2000; PubMed Scopus Google Scholar). In by intracellular cholesterol and lipid is to be with have that of which and the of in T. A. B. Repa J.J. Lobaccaro J.M. J.R. Mangelsdorf D.J. Heyman R.A. J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google of monocytes and cell to and of oxysterols and oxidized expression and that are with normal cell function and to A.J. Nature. 2000; PubMed Scopus Google Scholar). include in the expression of genes that are in regulating lipid and have that the expression of pro-inflammatory such as tumor necrosis factor-α and factor are in in response to or oxysterols Ma, J. Google Scholar, S. B. J. Biol. 1996; 16: PubMed Scopus Google Scholar, T.A. J. Lipid Res. Full Text PDF PubMed Google Scholar, Full Text Full Text PDF PubMed Scopus Google Scholar). have demonstrated of and oxysterols in cells and cells S. M. J. J. Biol. 1997; PubMed Scopus Google Scholar, S. Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The described and of the and cells in the of the A.J. Nature. 2000; PubMed Scopus Google Scholar). and necrosis that to the J.L. Cell. Full Text Full Text PDF PubMed Scopus Google ligands for and may oxysterols that LXRα (6Brown A.J. Dean R.T. Jessup W. J. Lipid Res. 1996; 37: 320-335Abstract Full Text PDF PubMed Google Scholar), a role for LXR and LXR in cytokine production in been we that of the ligand 22(R)-HC to peripheral human monocytes and to monocytic THP-1 in the of results in the specific and production of a key pro-inflammatory and pro-apoptotic show that TNF-α production occurs via a novel two-step that involves an initial induction of TNF-α and intracellular protein accumulation mediated by LXRα/RXRα binding to an in the TNF-α and cell release of TNF-α protein via a separable 9cRA-dependent, which requires de novo transcription and protein synthesis. a novel role for LXR and oxysterols in function and identify a unique pathway of cytokine production in role of LXRα in that of lipid accumulation and efflux and in to in monocytes and and to conditions such as transcription factor T. A. B. Repa J.J. Lobaccaro J.M. J.R. Mangelsdorf D.J. Heyman R.A. J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, A. B.A. L. Evans R.M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, A. L. Evans R.M. PubMed Scopus Google L. Evans R.M. Cell. 1998; 93: Full Text Full Text PDF PubMed Scopus Google Scholar). The findings identify a new and potentially role for LXRα and oxysterols in monocytes and by that LXRα and ligands TNF-α synthesis. we show that cell release of TNF-α protein in response to LXR is mediated via an and separable that is by the retinoid 9cRA that Our findings are in that of TNF-α specific to and the of pro-inflammatory such as and with the and in cells to such as The that of LXR and 9cRA in a novel and pathway of cytokine induction that may be specific to and inhibitor demonstrated that the TNF-α promoter is a target for by binding of LXRα/RXRα to a at position −879 of the TNF-α promoter. In to to be of the promoter that are for LXR a promoter that the activated by to a that the that requires the of a response element with transcription to LXRα and and with transcription factors the of and with that are to be important for TNF-α plays a and role in and and production of TNF-α is by and that to and of TNF-α protein M. S. M. B. Chen S. M. J. 2000; PubMed Scopus Google Scholar, J.L. R. J. Cell. Biol. PubMed Scopus Google W. A. D.A. J.L. J. Res. 2000; PubMed Scopus Google Scholar). Our findings identify a novel pathway of that is by and order-of-addition experiments that 9cRA as a step to induction of TNF-α and protein synthesis. step is of TNF-α release in the of the LXR requires de novo transcription and protein to by and The that potentially of the of or factors for release of TNF-α is for such a in a that 9cRA and the of from cells 1997; Full Text PDF PubMed Scopus Google Scholar). been that TNF-α in activated is in the and is from intracellular by W. A. D.A. J.L. J. Res. 2000; PubMed Scopus Google Scholar), mediated by protein K. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). be of to the and in release of TNF-α and is specific to TNF-α in response to and involves nuclear hormone receptors such as of monocytes the and lipid-loaded cells of by receptors such as and is of the in A.J. Nature. 2000; PubMed Scopus Google Scholar, Jessup W. J. Biol. 1999; PubMed Scopus Google Scholar). In by cholesterol of and is to be findings that LXR and and the of in T. A. B. Repa J.J. Lobaccaro J.M. J.R. Mangelsdorf D.J. Heyman R.A. J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google are with In of pro-inflammatory including are and necrosis in to and A.J. Nature. 2000; PubMed Scopus Google Scholar). have that oxysterols A.J. Jessup W. 1999; Full Text Full Text PDF PubMed Scopus Google and that of cells as as TNF-α M. B. J. B. S. J. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, A. S. J. Biol. 2000; PubMed Scopus Google Scholar). the expression of TNF-α by in the of the with that LXR a pro-inflammatory In specific of TNF-α expression in the with cholesterol to of by of a of TNF-α expression be a TNF-α to the by cytokine production from TNF-α and and the of findings may and physiological that are to of the In is that of TNF-α induction from be specific physiological a mediated by compounds such as is to cell release of we that the human TNF-α is a target for LXRα in monocytes and identify a unique and multistep pathway of TNF-α production in Our findings reveal a potentially important new dimension to the physiological role of to the consequence of findings to normal function and Liver X receptors (LXRα (NR1H3) and LXRβ (NR1H2)) 1The abbreviations used are:LXRliver X receptor22(R)-HC22(R)-hydroxycholesterol22(S)-HC22(S)-hydroxycholesterol9cRA9-cis-retinoic acidLXRELXR-response elementoxLDLoxidized low density lipoproteinRXR9-cis-retinoic acid receptor (retinoid X receptor)TNF-αtumor necrosis factor-αILinterleukinLPSlipopolysaccharideCMVcytomegalovirusELISAenzyme-linked immunosorbent assayApoEapolipoprotein EMTVmurine mammary tumor virus 1The abbreviations used are:LXRliver X receptor22(R)-HC22(R)-hydroxycholesterol22(S)-HC22(S)-hydroxycholesterol9cRA9-cis-retinoic acidLXRELXR-response elementoxLDLoxidized low density lipoproteinRXR9-cis-retinoic acid receptor (retinoid X receptor)TNF-αtumor necrosis factor-αILinterleukinLPSlipopolysaccharideCMVcytomegalovirusELISAenzyme-linked immunosorbent assayApoEapolipoprotein EMTVmurine mammary tumor virus are recently described members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are important in the regulation of genes that govern cholesterol homeostasis in the liver and cholesterol efflux from peripheral tissues. LXRs are bound by and activated by specific cholesterol metabolites, including oxysterols, and regulate the expression of target genes by binding to specific promoter response elements (LXREs) in association with the obligate heterodimerization partner, retinoid X receptor (RXR), the receptor for 9-cis-retinoic acid (9cRA) (1Repa J.J. Mangelsdorf D.J. Annu. Rev. Cell Dev. Biol. 2000; 16: 459-481Crossref PubMed Scopus (598) Google Scholar). Natural ligands for LXR include 22(R)-hydroxycholesterol (22(R)-HC), 24(S),25-epoxycholesterol, and 25-hydroxycholesterol (2Janowski B.A. Willy P.J. Devi T.R. Falck J.R. Mangelsdorf D.J. Nature. 1996; 383: 728-731Crossref PubMed Scopus (1440) Google Scholar, 3Lehmann J.M. Kliewer S.A. Moore L.B. Smith-Oliver T.A. Oliver B.B., Su, J.L. Sundseth S.S. Winegar D.A. Blanchard D.E. Spencer T.A. Willson T.M. J. Biol. Chem. 1997; 272: 3137-3140Abstract Full Text Full Text PDF PubMed Scopus (1028) Google Scholar, 4Janowski B.A. Grogan M.J. Jones S.A. Wisely G.B. Kliewer S.A. Corey E.J. Mangelsdorf D.J. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 266-271Crossref PubMed Scopus (780) Google Scholar), compounds that have been found free in serum and in association with atherogenic oxidized low density lipoprotein (oxLDL) particles (5Dixon R. Furutachi T. Lieberman S. Biochem. Biophys. Res. Commun. 1970; 40: 161-165Crossref PubMed Scopus (30) Google Scholar, 6Brown A.J. Dean R.T. Jessup W. J. Lipid Res. 1996; 37: 320-335Abstract Full Text PDF PubMed Google Scholar, 7Kandutsch A.A. Chen H.W. Heiniger H.J. Science. 1978; 201: 498-501Crossref PubMed Scopus (403) Google Scholar). In the liver, LXRα serves as a sterol sensor and regulates the expression of genes that influence cholesterol metabolism and homeostasis, including the genes encoding cholesterol 7α-hydroxylase, which controls the cholesterol/bile acid synthetic pathway, and sterol regulatory element-binding protein-1c, a key transcription factor that regulates expression of genes important in fatty acid biosynthesis (6Brown A.J. Dean R.T. Jessup W. J. Lipid Res. 1996; 37: 320-335Abstract Full Text PDF PubMed Google Scholar,8Willy P.J. Umesono K. Ong E.S. Evans R.M. Heyman R.A. Mangelsdorf D.J. Genes Dev. 1995; 9: 1033-1045Crossref PubMed Scopus (908) Google Scholar, 9Peet D.J. Turley S.D., Ma, W. Janowski B.A. Lobaccaro J.M. Hammer R.E. Mangelsdorf D.J. Cell. 1998; 93: 693-704Abstract Full Text Full Text PDF PubMed Scopus (1230) Google Scholar, 10Schultz J.R., Tu, H. Luk A. Repa J.J. Medina J.C., Li, L. Schwendner S. Wang S. Thoolen M. Mangelsdorf D.J. Lustig K.D. Shan B. Genes Dev. 2000; 14: 2831-2838Crossref PubMed Scopus (1380) Google Scholar, 11Repa J.J. Liang G., Ou, J. Bashmakov Lobaccaro J.M. Shan B. J.L. Mangelsdorf D.J. Genes Dev. 2000; 14: PubMed Scopus Google Scholar). have that LXRα is for normal cholesterol homeostasis and of cholesterol in D.J. Turley S.D., Ma, W. Janowski B.A. Lobaccaro J.M. Hammer R.E. Mangelsdorf D.J. Cell. 1998; 93: 693-704Abstract Full Text Full Text PDF PubMed Scopus (1230) Google Scholar). liver X receptor 22(R)-hydroxycholesterol 9-cis-retinoic acid element oxidized low density lipoprotein 9-cis-retinoic acid receptor (retinoid X tumor necrosis factor-α immunosorbent mammary tumor virus liver X receptor 22(R)-hydroxycholesterol 9-cis-retinoic acid element oxidized low density lipoprotein 9-cis-retinoic acid receptor (retinoid X tumor necrosis factor-α immunosorbent mammary tumor virus that LXRα plays a role in by regulating cholesterol efflux from lipid-loaded is by induction of genes encoding the and which cholesterol that and free cholesterol efflux from monocytes and lipid-loaded Wang J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, K. R.M. Biochem. Biophys. Res. Commun. 2000; PubMed Scopus Google Scholar, A. Repa J.J. Lobaccaro J.M. A. Mangelsdorf D.J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, A. B.A. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar). cholesterol is to density and to the liver is to and (1Repa J.J. Mangelsdorf D.J. Annu. Rev. Cell Dev. Biol. 2000; 16: 459-481Crossref PubMed Scopus (598) Google Scholar). The key role of LXR as a in the cholesterol efflux and intracellular cholesterol is by the findings that the genes encoding which is for density lipoprotein is a target of LXR B.A. Repa J.J. Mangelsdorf D.J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The role of LXRα in regulating cholesterol in is of disease lipid accumulation in the of is of to the and of and and particles in that have the lipid-loaded cells that the fatty of A.J. Nature. 2000; PubMed Scopus Google Scholar). In by intracellular cholesterol and lipid is to be with have that of which and the of in T. A. B. Repa J.J. Lobaccaro J.M. J.R. Mangelsdorf D.J. Heyman R.A. J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). of monocytes and cell to and of oxysterols and oxidized expression and that are with normal cell function and to A.J. Nature. 2000; PubMed Scopus Google Scholar). include in the expression of genes that are in regulating lipid and have that the expression of pro-inflammatory such as tumor necrosis factor-α and factor are in in response to or oxysterols Ma, J. Google Scholar, S. B. J. Biol. 1996; 16: PubMed Scopus Google Scholar, T.A. J. Lipid Res. Full Text PDF PubMed Google Scholar, Full Text Full Text PDF PubMed Scopus Google Scholar). have demonstrated of and oxysterols in cells and cells S. M. J. J. Biol. 1997; PubMed Scopus Google Scholar, S. Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The described and of the and cells in the of the A.J. Nature. 2000; PubMed Scopus Google Scholar). and necrosis that to the J.L. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). ligands for and may oxysterols that LXRα (6Brown A.J. Dean R.T. Jessup W. J. Lipid Res. 1996; 37: 320-335Abstract Full Text PDF PubMed Google Scholar), a role for LXR and LXR in cytokine production in been we that of the ligand 22(R)-HC to peripheral human monocytes and to monocytic THP-1 in the of results in the specific and production of a key pro-inflammatory and pro-apoptotic show that TNF-α production occurs via a novel two-step that involves an initial induction of TNF-α and intracellular protein accumulation mediated by LXRα/RXRα binding to an in the TNF-α and cell release of TNF-α protein via a separable 9cRA-dependent, which requires de novo transcription and protein synthesis. a novel role for LXR and oxysterols in function and identify a unique pathway of cytokine production in role of LXRα in that of lipid accumulation and efflux and in to in monocytes and and to conditions such as transcription factor T. A. B. Repa J.J. Lobaccaro J.M. J.R. Mangelsdorf D.J. Heyman R.A. J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, A. B.A. L. Evans R.M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, A. L. Evans R.M. PubMed Scopus Google L. Evans R.M. Cell. 1998; 93: Full Text Full Text PDF PubMed Scopus Google Scholar). The findings identify a new and potentially role for LXRα and oxysterols in monocytes and by that LXRα and ligands TNF-α synthesis. we show that cell release of TNF-α protein in response to LXR is mediated via an and separable that is by the retinoid 9cRA that Our findings are in that of TNF-α specific to and the of pro-inflammatory such as and with the and in cells to such as The that of LXR and 9cRA in a novel and pathway of cytokine induction that may be specific to and inhibitor demonstrated that the TNF-α promoter is a target for by binding of LXRα/RXRα to a at position −879 of the TNF-α promoter. In to to be of the promoter that are for LXR a promoter that the activated by to a that the that requires the of a response element with transcription to LXRα and and with transcription factors the of and with that are to be important for TNF-α plays a and role in and and production of TNF-α is by and that to and of TNF-α protein M. S. M. B. Chen S. M. J. 2000; PubMed Scopus Google Scholar, J.L. R. J. Cell. Biol. PubMed Scopus Google W. A. D.A. J.L. J. Res. 2000; PubMed Scopus Google Scholar). Our findings identify a novel pathway of that is by and order-of-addition experiments that 9cRA as a step to induction of TNF-α and protein synthesis. step is of TNF-α release in the of the LXR requires de novo transcription and protein to by and The that potentially of the of or factors for release of TNF-α is for such a in a that 9cRA and the of from cells 1997; Full Text PDF PubMed Scopus Google Scholar). been that TNF-α in activated is in the and is from intracellular by W. A. D.A. J.L. J. Res. 2000; PubMed Scopus Google Scholar), mediated by protein K. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). be of to the and in release of TNF-α and is specific to TNF-α in response to and involves nuclear hormone receptors such as of monocytes the and lipid-loaded cells of by receptors such as and is of the in A.J. Nature. 2000; PubMed Scopus Google Scholar, Jessup W. J. Biol. 1999; PubMed Scopus Google Scholar). In by cholesterol of and is to be findings that LXR and and the of in T. A. B. Repa J.J. Lobaccaro J.M. J.R. Mangelsdorf D.J. Heyman R.A. J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google are with In of pro-inflammatory including are and necrosis in to and A.J. Nature. 2000; PubMed Scopus Google Scholar). have that oxysterols A.J. Jessup W. 1999; Full Text Full Text PDF PubMed Scopus Google and that of cells as as TNF-α M. B. J. B. S. J. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, A. S. J. Biol. 2000; PubMed Scopus Google Scholar). the expression of TNF-α by in the of the with that LXR a pro-inflammatory In specific of TNF-α expression in the with cholesterol to of by of a of TNF-α expression be a TNF-α to the by cytokine production from TNF-α and and the of findings may and physiological that are to of the In is that of TNF-α induction from be specific physiological a mediated by compounds such as is to cell release of we that the human TNF-α is a target for LXRα in monocytes and identify a unique and multistep pathway of TNF-α production in Our findings reveal a potentially important new dimension to the physiological role of to the consequence of findings to normal function and The role of LXRα in that of lipid accumulation and efflux and in to in monocytes and and to conditions such as transcription factor T. A. B. Repa J.J. Lobaccaro J.M. J.R. Mangelsdorf D.J. Heyman R.A. J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, A. B.A. L. Evans R.M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, A. L. Evans R.M. PubMed Scopus Google L. Evans R.M. Cell. 1998; 93: Full Text Full Text PDF PubMed Scopus Google Scholar). The findings identify a new and potentially role for LXRα and oxysterols in monocytes and by that LXRα and ligands TNF-α synthesis. we show that cell release of TNF-α protein in response to LXR is mediated via an and separable that is by the retinoid 9cRA that Our findings are in that of TNF-α specific to and the of pro-inflammatory such as and with the and in cells to such as The that of LXR and 9cRA in a novel and pathway of cytokine induction that may be specific to and inhibitor demonstrated that the TNF-α promoter is a target for by binding of LXRα/RXRα to a at position −879 of the TNF-α promoter. In to to be of the promoter that are for LXR a promoter that the activated by to a that the that requires the of a response element with transcription to LXRα and and with transcription factors the of and with that are to be important for TNF-α TNF-α plays a and role in and and production of TNF-α is by and that to and of TNF-α protein M. S. M. B. Chen S. M. J. 2000; PubMed Scopus Google Scholar, J.L. R. J. Cell. Biol. PubMed Scopus Google W. A. D.A. J.L. J. Res. 2000; PubMed Scopus Google Scholar). Our findings identify a novel pathway of that is by and order-of-addition experiments that 9cRA as a step to induction of TNF-α and protein synthesis. step is of TNF-α release in the of the LXR requires de novo transcription and protein to by and The that potentially of the of or factors for release of TNF-α is for such a in a that 9cRA and the of from cells 1997; Full Text PDF PubMed Scopus Google Scholar). been that TNF-α in activated is in the and is from intracellular by W. A. D.A. J.L. J. Res. 2000; PubMed Scopus Google Scholar), mediated by protein K. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). be of to the and in release of TNF-α and is specific to TNF-α in response to and involves nuclear hormone receptors such as The of monocytes the and lipid-loaded cells of by receptors such as and is of the in A.J. Nature. 2000; PubMed Scopus Google Scholar, Jessup W. J. Biol. 1999; PubMed Scopus Google Scholar). In by cholesterol of and is to be findings that LXR and and the of in T. A. B. Repa J.J. Lobaccaro J.M. J.R. Mangelsdorf D.J. Heyman R.A. J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google are with In of pro-inflammatory including are and necrosis in to and A.J. Nature. 2000; PubMed Scopus Google Scholar). have that oxysterols A.J. Jessup W. 1999; Full Text Full Text PDF PubMed Scopus Google and that of cells as as TNF-α M. B. J. B. S. J. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, A. S. J. Biol. 2000; PubMed Scopus Google Scholar). the expression of TNF-α by in the of the with that LXR a pro-inflammatory In specific of TNF-α expression in the with cholesterol to of by of a of TNF-α expression be a TNF-α to the by cytokine production from TNF-α and and the of findings may and physiological that are to of the In is that of TNF-α induction from be specific physiological a mediated by compounds such as is to cell release of In we that the human TNF-α is a target for LXRα in monocytes and identify a unique and multistep pathway of TNF-α production in Our findings reveal a potentially important new dimension to the physiological role of to the consequence of findings to normal function and J. and M. for TNF-α and J. of for and Mangelsdorf of for to for with of the K. and R. for and

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