title: Induction of CCL13 expression in synovial fibroblasts highlights a significant role of oncostatin M in rheumatoid arthritis.
abstract: OBJECTIVE
  To investigate the molecular mechanisms of CCL13/monocyte chemoattractant protein 4 (MCP-4) chemokine expression through proinflammatory cytokines in different primary human fibroblasts and the contribution of CCL13 to monocyte migration.
  
  
  METHODS
  Using RNase protection assays and enzyme-linked immunosorbent assays, we quantified the expression of CCL13 compared with that of CCL2/MCP-1 in primary human fibroblasts. Boyden chamber assays were performed to determine the importance of CCL13 for migration of primary monocytes. Pharmacologic inhibitors as well as small interfering RNA knockdown approaches were used to investigate the signaling pathways regulating CCL13 expression.
  
  
  RESULTS
  The interleukin-6 (IL-6)-type cytokine oncostatin M (OSM) was a powerful inducer of CCL13 expression in primary synovial fibroblasts from patients with rheumatoid arthritis (RA) as well as those from healthy control subjects but not in other types of fibroblasts. Neither IL-6 nor tumor necrosis factor alpha could stimulate the expression of CCL13 in synovial fibroblasts; IL-1beta was a very weak inducer. Synovial fibroblasts from patients with RA constitutively produced low amounts of CCL13, which was partially dependent on constitutive production of OSM. By investigating the underlying molecular mechanism, we identified STAT-5, ERK-1/2, and p38 as critical factors involved in OSM-dependent transcription and messenger RNA stabilization of CCL13.
  
  
  CONCLUSIONS
  In contrast to other prominent cytokines involved in the pathogenesis of RA, OSM can strongly up-regulate the expression of CCL13, a chemokine recently identified in the synovial fluid of patients with RA. Despite potent OSM-induced signal transduction in all types of fibroblasts analyzed, only synovial fibroblasts secreted CCL13, which might be indicative of tissue-specific imprinting of different fibroblasts during development.
authors: University of Würzburg, Würzburg, Germany.
authors: Christoph
authors: C
authors: Hintzen
authors: Saskia
authors: S
authors: Quaiser
authors: Thomas
authors: T
authors: Pap
authors: Peter C
authors: PC
authors: Heinrich
authors: Heike M
authors: HM
authors: Hermanns
mesh_terms: D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018945:Monocyte Chemoattractant Proteins / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D053683:Oncostatin M / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C099677:CCL13 protein, human; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D015850:Interleukin-6; D018945:Monocyte Chemoattractant Proteins; D050799:STAT5 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D053683:Oncostatin M; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases