Fibroblasts are major contributors to and regulators of inflammation and dominant producers of interleukin-6 (IL-6) in inflammatory diseases like rheumatoid arthritis. Yet, compared to leukocytes, the regulation of inflammatory pathways in fibroblasts is largely unknown. Here, we report that analyses of genes coordinately upregulated with IL-6 pointed to STAT4 and leukemia inhibitory factor (LIF) as potentially linked. Gene silencing revealed that STAT4 was required for IL-6 transcription. STAT4 was recruited to the IL-6 promoter after fibroblast activation, and LIF receptor (LIFR) and STAT4 formed a molecular complex that, together with JAK1 and TYK2 kinases, controlled STAT4 activation. Importantly, a positive feedback loop involving autocrine LIF, LIFR, and STAT4 drove sustained IL-6 transcription. Besides IL-6, this autorine loop also drove the production of other key inflammatory factors including IL-8, granulocyte-colony stimulating factor (G-CSF), IL-33, IL-11, IL-1α, and IL-1β. These findings define the transcriptional regulation of fibroblast-mediated inflammation as distinct from leukocytes.
Pubmed ID: 28228280 RIS Download
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View all literature mentionsDatabase which provides on-line searching of microarray datasets generated from rat spinal cord after contusion injury. Both the primary injury site and a site 5 mm distal to the injury site were assayed. Tissue was obtained from Long Evans rats subject to spinal cord contusion injury using the MASCIS impactor (formerly known as the NYU impactor). RNA expression was assayed at the site of injury and distal to the site of injury using the Affymetrix Rat Neuro U34 chip.
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