title: Inhibition of IGF-I-related intracellular signaling pathways by proinflammatory cytokines in growth plate chondrocytes.
abstract: BACKGROUND
  Children with chronic inflammatory diseases suffer from severe growth failure associated with resistance toward the anabolic action of insulin-like growth factor I (IGF-I). We hypothesized that proinflammatory cytokines interfere with IGF-I signaling.
  
  
  METHODS
  We used the mesenchymal chondrogenic cell line RCJ3.1C5.18 as a model of the growth plate. Cell proliferation was assessed by [(3)H]-thymidine-uptake and differentiation by gene expression (quantitative reverse-transcriptase PCR) of specific differentiation markers. Key signaling molecules of the respective IGF-I-related intracellular pathways were determined by western immunoblotting.
  
  
  RESULTS
  Coincubation of the proinflammatory cytokines interleukin (IL)-1β (10 ng/ml), IL-6 (100 ng/ml), or tumor necrosis factor-α (50 ng/ml) with IGF-I inhibited IGF-I-driven cell proliferation by 50%, while baseline cell proliferation was not altered. These cytokines attenuated the IGF-I-induced phosphorylation of AKT as a key signaling molecule of the phosphatidylinositol-3 kinase pathway by 30-50% and the phosphorylation of ERK as a key signaling molecule of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by 50-75%. Also, IGF-I-enhanced chondrocyte differentiation was inhibited by these proinflammatory cytokines.
  
  
  CONCLUSIONS
  The insensitivity toward the anabolic action of IGF-I in the growth plate in conditions of chronic inflammation is partially due to inhibition of IGF-I-specific signaling pathways by proinflammatory cytokines, which affect both IGF-I-driven chondrocyte proliferation and differentiation.
authors.affiliation: Department of Pediatrics I, University Children's Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Choukair
authors.affiliation: Department of Pediatrics I, University Children's Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Hügel
authors.affiliation: Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Sander
authors.affiliation: Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Uhlmann
authors.affiliation: Department of Pediatrics I, University Children's Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Tönshoff
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020219:Chondrogenesis / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006132:Growth Plate / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D019382:Human Growth Hormone / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016207:Cytokines; C583557:IGF1 protein, human; C508585:IL1B protein, human; C508600:IL6 protein, human; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases