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FRI0031 Tyrosine kinase induced fibrosis: implications for systemic sclerosis
  1. S. O’reilly1,
  2. J. Van Laar1
  1. 1Musculoskeletal Research Group, Newcastle University, Newcastle, United Kingdom


Background Systemic Sclerosis (SSc) is an autoimmune disease characterised by autoimmunity, inflammation, vascular abnormalities and fibrosis. There is a clear link between inflammation and fibrosis however, the mediators and the downstream signalling pathways remain to be elucidated. IL-6 is a pro-fibrotic molecule elevated in SSc serum and is also elevated in the affected tissues. The molecule can signal through both classic signalling and also ‘trans-signalling’ to initiate a signaling cascade that results in activation of pro-fibrotic genes. Upstream of these genes after ligand binding is the inital event of janus kinase activation. The janus kinases are non-receptor tyrosine kinases that activate STATs resulting in target gene expression. JAK2 has previously been implicated in fibrosis and in particular SSc. Ruxolitinib is a tyrosine kinase inhibitor approved for the treatment of myleofibrosis.

Objectives The aim of this study was to determine the effects of JAK2 inhibition on collagen production after ligand stimulation using Ruxolitinib.

Methods Primary human dermal fibroblasts were cultured in vitro to confluence and then treated with the cytokines IL-6 and sIL-R either alone or in combination, plus cultures were also treated with a JAK2 pharmacological inhibitor for 24 hours. After 24 hours cells were harvested RNA ioslated and RT performed. Q-RT-PCR was performed with primers specific for collagen 1A1 gene and then normalised to endogenous housekeeper 18s and compared to untreated cultures. 18s was found to be consistent among treatment groups. In other experiments IL-13 at various concentrations was added to the dermal fibroblast cultures and q-RT-PCR was performed.

Results Dermal fibroblasts upregulated collagen1A1 transcripts in response to IL-6 and sIL-6R but not either alone, suggesting the primary mechanism was trans signalling. This IL-6-induction collagen transcription cold be abrogated by the pharmacological agent Ruxolitinib. IL-13 also induced collagen expression in dermal fibroblasts and this, to a lesser degree, could also be inhibited by ruxolitinib pre-treatment.

Conclusions IL-6 trans signalling-stimulated collagen production is mediated by JAKs and selective blockade of JAK2 also reduced the pro-fibrotic molecule IL-13s collagen-inducing effect. Blokade of JAK2 maybe a new therapeutic target in SSc.

Acknowledgements JGW Patterson.

Disclosure of Interest None Declared

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