title: Interleukin-1 has opposing effects on connective tissue growth factor and tenascin-C expression in human cardiac fibroblasts.
abstract: Cardiac fibroblasts (CF) play a central role in the repair and remodeling of the heart following injury and are important regulators of inflammation and extracellular matrix (ECM) turnover. ECM-regulatory matricellular proteins are synthesized by several myocardial cell types including CF. We investigated the effects of pro-inflammatory cytokines on matricellular protein expression in cultured human CF. cDNA array analysis of matricellular proteins revealed that interleukin-1α (IL-1α, 10ng/ml, 6h) down-regulated connective tissue growth factor (CTGF/CCN2) mRNA by 80% and up-regulated tenascin-C (TNC) mRNA levels by 10-fold in human CF, without affecting expression of thrombospondins 1-3, osteonectin or osteopontin. Western blotting confirmed these changes at the protein level. In contrast, tumor necrosis factor α (TNFα) did not modulate CCN2 expression and had only a modest stimulatory effect on TNC levels. Signaling pathway inhibitor studies suggested an important role for the p38 MAPK pathway in suppressing CCN2 expression in response to IL-1α. In contrast, multiple signaling pathways (p38, JNK, PI3K/Akt and NFκB) contributed to IL-1α-induced TNC expression. In conclusion, IL-1α reduced CCN2 expression and increased TNC expression in human CF. These observations are of potential value for understanding how inflammation and ECM regulation are linked at the level of the CF.
authors: Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds LS2 9JT, UK.
authors: Azhar
authors: A
authors: Maqbool
authors: Karen E
authors: KE
authors: Hemmings
authors: David J
authors: DJ
authors: O'Regan
authors: Stephen G
authors: SG
authors: Ball
authors: Karen E
authors: KE
authors: Porter
authors: Neil A
authors: NA
authors: Turner
mesh_terms: D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D053582:Interleukin-1alpha / Q000502:physiology*; D009206:Myocardium / Q000473:pathology; D058628:Myofibroblasts / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019063:Tenascin / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: C526317:CCN2 protein, human; C508584:IL1A protein, human; D053582:Interleukin-1alpha; D012333:RNA, Messenger; D019063:Tenascin; D014409:Tumor Necrosis Factor-alpha; D055513:Connective Tissue Growth Factor