Nguyen, Hung N., Noss, Erika H., Mizoguchi, Fumitaka, Huppertz, Christine, Wei, Kevin S., Watts, Gerald F.M. and Brenner, Michael B. (2017) Autocrine Loop Involving IL-6 Family Member LIF, LIF Receptor, and STAT4 Drives Sustained Fibroblast Production of Inflammatory Mediators. Immunity, 46 (2). pp. 220-232. ISSN 10974180

Abstract

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.

Item Type:	Article
Keywords:	fibroblasts IL-33 IL-6 IL-8 interleukin-33 interleukin-6 interleukin-8 leukemia inhibitor factor leukemia inhibitor factor receptor LIF LIFR rheumatoid arthritis signal transducer and activator of transcription 4 STAT4 stromal cells synovium
Date Deposited:	25 Oct 2017 00:45
Last Modified:	25 Jan 2019 00:45
URI:	https://oak.novartis.com/id/eprint/32473