title: Differential modes of regulation of interleukin-1beta expression by extracellular matrices.
abstract: Extracellular matrices (ECMs) can stimulate human monocytic cells to express interleukin-1beta (IL-1beta), a proinflammatory cytokine implicated in the regulation of tissue inflammation. In this study, we explored the intracellular mechanisms responsible for ECM induction of IL-1beta using human promonocytic U937 cells transfected with the full-length human IL-1beta gene promoter connected to a reporter gene. Using this system, we demonstrated that the ECM molecules fibronectin (FN), type I collagen (Coll), fibrin (Fb) and laminin (Lm) induced transcription of the IL-1beta gene (which was associated with a modest increase in IL-1beta protein secretion) in suspended cells, when used in their soluble monomeric form. This effect was mimicked or blocked by anti-integrin monoclonal antibodies (mAbs) and was dependent on the activation of protein kinase C (PKC). Three of the ECMs tested (FN, Coll and Fb) induced the activation of mitogen-activated protein kinases (MAPKs), whereas Lm had no effect. FN, Coll and Fb (but not Lm) also induced DNA binding of the transcription factor activator protein-1 (AP-1), but not that of nuclear factor-kappaB. Co-transfection of U937 cells with a competing AP-1 oligomer blocked the IL-1beta response induced by FN, but not that induced by the other ECMs. By inhibiting AP-1 translocation, glucocorticoids also blocked the FN-induced response, but not that of the other ECMs. These studies suggest that the signalling pathways which mediate ECM induction of IL-1beta expression in human monocytic cells converge at the level of PKC activation. However, they diverge in other aspects, as demonstrated by the differential activation of MAPKs and the need for diverse transcription factors.
authors.affiliation: Pulmonary & Critical Care Division, Department of Medicine, Atlanta Veterans Affairs Medical Center, Decatur, GA 30033, USA.
authors.forename: J
authors.initials: J
authors.lastname: Roman
authors.forename: J D
authors.initials: JD
authors.lastname: Ritzenthaler
authors.forename: R L
authors.initials: RL
authors.lastname: Perez
authors.forename: S L
authors.initials: SL
authors.lastname: Roser
mesh_terms: D000287:Administration, Topical; D000730:Androstadienes / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002460:Cell Line; D003094:Collagen / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects / Q000276:immunology*; D016326:Extracellular Matrix Proteins / Q000494:pharmacology*; D005337:Fibrin / Q000494:pharmacology; D005353:Fibronectins / Q000494:pharmacology; D000068298:Fluticasone; D005938:Glucocorticoids; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics* / Q000378:metabolism; D007797:Laminin / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D013268:Stimulation, Chemical; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D005938:Glucocorticoids; D007375:Interleukin-1; D007797:Laminin; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D005337:Fibrin; D003094:Collagen; D000068298:Fluticasone; D020928:Mitogen-Activated Protein Kinases