title: CD40L induces inflammation and adipogenesis in adipose cells--a potential link between metabolic and cardiovascular disease.
abstract: CD40L figures prominently in atherogenesis. Recent data demonstrate elevated levels of sCD40L in the serum of patients with the metabolic syndrome (MS). This study investigated the role of CD40L in pro-inflammatory gene expression and cellular differentiation in adipose tissue to obtain insight into mechanisms linking the MS with atherosclerosis. Human adipocytes and preadipocytes expressed CD40 but not CD40L. Stimulation with recombinant CD40L or membranes over-expressing CD40L induced a time- and dose-dependent expression of IL-6, MCP-1, IL-8, and PAI-1. Supernatants of CD40L-stimulated adipose cells activated endothelial cells, suggesting a systemic functional relevance of our findings. Neutralising antibodies against CD40L attenuated these effects substantially. Signalling studies revealed the involvement of mitogen-activated protein kinases and NFkB. Furthermore, stimulation with CD40L resulted in enhanced activation of C/EBPa and PPARg and promoted adipogenesis of preadipose cells in the presence and absence of standard adipogenic conditions. Finally, patients suffering from the metabolic syndrome with high levels of sCD40L also displayed high levels of IL-6, in line with the concept that CD40L may induce the expression of inflammatory cytokines in vivo in this population. Our data reveal potent metabolic functions of CD40L aside from its known pivotal pro-inflammatory role within plaques. Our data suggest that CD40L may mediate risk at the interface of metabolic and atherothrombotic disease.
authors.affiliation: Department of Cardiology, University of Freiburg, Freiburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Missiou
authors.forename: Dennis
authors.initials: D
authors.lastname: Wolf
authors.forename: Isabel
authors.initials: I
authors.lastname: Platzer
authors.forename: Sandra
authors.initials: S
authors.lastname: Ernst
authors.forename: Carina
authors.initials: C
authors.lastname: Walter
authors.forename: Philipp
authors.initials: P
authors.lastname: Rudolf
authors.forename: Katja
authors.initials: K
authors.lastname: Zirlik
authors.forename: Natascha
authors.initials: N
authors.lastname: Köstlin
authors.forename: Florian K
authors.initials: FK
authors.lastname: Willecke
authors.forename: Christian
authors.initials: C
authors.lastname: Münkel
authors.forename: Uwe
authors.initials: U
authors.lastname: Schönbeck
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.forename: Nerea
authors.initials: N
authors.lastname: Varo
authors.forename: Andreas
authors.initials: A
authors.lastname: Zirlik
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000276:immunology* / Q000378:metabolism; D050156:Adipogenesis; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D018932:Chemokine CCL2 / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000378:metabolism; D024821:Metabolic Syndrome / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C111835:CCL2 protein, human; D019013:CD40 Antigens; C515848:CEBPA protein, human; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D017077:Culture Media, Conditioned; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D047495:PPAR gamma; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D011994:Recombinant Proteins; C051321:SERPINE1 protein, human; D023201:CD40 Ligand; D020928:Mitogen-Activated Protein Kinases