Clinical and pathological significance of interleukin 6 overexpression in systemic sclerosis
- Korsa Khan,
- Shiwen Xu,
- Svetlana Nihtyanova,
- Emma Derrett-Smith,
- David Abraham,
- Christopher P Denton,
- Voon H Ong
- Centre for Rheumatology and Connective Tissue Diseases, UCL Medical School, Royal Free Campus, London, UK
- Correspondence to Dr Voon H Ong, Centre for Rheumatology and Connective Tissue Diseases, UCL Medical School, Royal Free Campus, London NW3 2PF, UK;
Contributors This study was designed by VO and CPD and all authors participated equally in the experimental work, analysis and interpretation of the data. The paper was written jointly by all authors and the final submitted version was approved by all authors.
- Received 24 October 2012
- Accepted 12 February 2012
- Published Online First 14 May 2012
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.
Conclusion 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.
Funding This study was funded by grants provided by Raynaud's & Scleroderma Association and the EULAR Orphan Diseases Programme (ODP) on Systemic Sclerosis.
Competing interests None.
Ethics approval This study was conducted with the approval of the Royal Free and Medical School Local Research Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.