title: Pro-inflammatory cytokines negatively regulate PPARγ mediated gene expression in both human and murine macrophages via multiple mechanisms.
abstract: PPARγ is a lipid activated transcription factor that connects lipid metabolism and immune function. It is known that anti-inflammatory cytokines, such as IL-4 that mediates the differentiation of alternatively activated macrophages, positively modulate PPARγ at three levels: by (1) increasing its expression (2), initiating a complex formation with STAT6 enhances its transcriptional activity and (3) increasing endogenous ligand production. On the other hand, PPARγ is known to inhibit inflammatory processes via transrepression. However, the impact of a pro-inflammatory cytokine milieu on PPARγ transcriptional activity in macrophages is less understood. We hypothesized that pro-inflammatory cytokines, such as IFNγ and TNFα negatively regulate PPARγ activity and sought to test this within human and murine macrophage models using both global and single target gene expression analysis. We found that IFNγ/TNFα inhibited PPARγ expression in human CD14+ monocytes derived macrophages and mouse bone marrow derived macrophages, but not in macrophages originating from CD34+ stem cells or Thp-1 monocytic cells. Irrespective of the model system, the ability of PPARγ to regulate gene expression was inhibited. Moreover, we demonstrated that in Thp-1 cells PPARγ in vitro DNA binding remained unchanged following IFNγ/TNFα pre-treatment. Taken together, our data suggest that pro-inflammatory conditions inhibit PPARγ activity at the gene expression level and propose two, mutually not exclusive models as mechanisms: (1) the level of PPARγ itself is down-regulated by the cytokines leading to loss of function, while (2) PPARγ itself remains associated with the DNA though unable to initiate gene expression. These findings support that inflammatory conditions skew the lipid sensing function of macrophages, further contributing to the vicious circle of metabolic disorders.
authors.affiliation: Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, University of Debrecen Medical and Health Science Center, H-4032 Debrecen, Nagyerdei krt 98, Hungary.
authors.forename: Zsuzsanna S
authors.initials: ZS
authors.lastname: Nagy
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Czimmerer
authors.forename: Attila
authors.initials: A
authors.lastname: Szanto
authors.forename: Laszlo
authors.initials: L
authors.lastname: Nagy
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000096:biosynthesis; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D050356:Lipid Metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013234:Stem Cells / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D004268:DNA-Binding Proteins; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; C508598:IL4 protein, human; D018950:Lipopolysaccharide Receptors; D047495:PPAR gamma; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma; D004247:DNA
keywords: Adrp; Arg; BMDM; Cytokine; FABP; Fizz1; GAPDH; IFN; IL; Inflammation; MHC-related protein; MR; Macrophage; Nuclear receptor; PPAR; RSG; STAT; TNF; Transcription; Ym-1; adipose differentiation-related protein; arginase; bone marrow derived macrophage; chitinase 3-like 3; fatty acid binding protein; found in inflammatory zone, also known as RELM-αor resistin-like molecule-α; glyceraldehyde 3-phosphate dehydrogenase; iNOS; inducible nitric oxide synthase; interferon; interleukin; oxLDL; oxidized low density lipoprotein; peroxisome proliferator-activated receptor; rosiglitazone; signal transducer and activator of transcription; tumor necrosis factor