title: Clinical and pathological significance of interleukin 6 overexpression in systemic sclerosis.
abstract: OBJECTIVE
  To determine the potential clinical and pathological significance of altered expression of interleukin 6 (IL-6) in systemic sclerosis (SSc).
  
  
  METHODS
  Serum IL-6 and soluble IL-6 receptor levels were measured in patients with SSc (n=68) and healthy controls (n=15). Associations between serum IL-6 level and C reactive protein, platelet count and key clinical outcomes in SSc were explored. Expression of IL-6 in skin biopsies was also examined and western blot and reverse transcription PCRanalysis were performed using cultured dermal fibroblasts. The effect of IL-6 trans-signalling on production of extracellular matrix proteins was assessed and downstream signalling pathways were examined using pharmacological inhibitors.
  
  
  RESULTS
  Serum IL-6 level was frequently elevated in patients with SSc, particularly in those with diffuse cutaneous SSc (dcSSc) with thrombocytosis and elevated acute phase markers. Prominent expression in the skin was observed in dermal fibroblasts, mononuclear cells and endothelial cells in patients with early dcSSc. In vitro experiments supported a potent profibrotic effect of IL-6 trans-signalling via the JAK2/STAT3 and ERK pathways. High IL-6 expression early in dcSSc appears to be associated with more severe skin involvement at 3 years and worse long-term survival than in those without elevated IL-6 levels.
  
  
  CONCLUSIONS
  Our results confirm the overexpression of IL-6 in dcSSc and support the potential of IL-6 as a surrogate marker for clinical outcome in this disease. The data also provide rationale for clinical studies targeting IL-6 trans-signalling as a potential antifibrotic therapy for SSc.
authors.affiliation: Centre for Rheumatology and Connective Tissue Diseases, UCL Medical School, Royal Free Campus, London, UK.
authors.forename: Korsa
authors.initials: K
authors.lastname: Khan
authors.forename: Shiwen
authors.initials: S
authors.lastname: Xu
authors.forename: Svetlana
authors.initials: S
authors.lastname: Nihtyanova
authors.forename: Emma
authors.initials: E
authors.lastname: Derrett-Smith
authors.forename: David
authors.initials: D
authors.lastname: Abraham
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Denton
authors.forename: Voon H
authors.initials: VH
authors.lastname: Ong
mesh_terms: D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis; D002478:Cells, Cultured; D020405:Dermis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D015850:Interleukin-6 / Q000097:blood* / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D019947:Receptors, Interleukin-6 / Q000097:blood / Q000235:genetics; D045743:Scleroderma, Diffuse / Q000097:blood* / Q000401:mortality / Q000473:pathology; D045745:Scleroderma, Limited / Q000097:blood* / Q000401:mortality / Q000473:pathology; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D015996:Survival Rate; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D015415:Biomarkers; D016326:Extracellular Matrix Proteins; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D002097:C-Reactive Protein