Autocrine Loop Involving IL-6 Family Member LIF, LIF Receptor, and STAT4 Drives Sustained Fibroblast Production of Inflammatory Mediators.

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.

• Authors: Hung N Nguyen, Erika H Noss, Fumitaka Mizoguchi, Christine Huppertz, Kevin S Wei, Gerald F M Watts, Michael B Brenner
• Journal: Immunity (Immunity) Vol. 46 Issue 2 Pg. 220-232 (02 21 2017) ISSN: 1097-4180 [Electronic] United States
• PMID: 28228280 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• IL6 protein, human
• Interleukin-6
• LIF protein, human
• Leukemia Inhibitory Factor
• Receptors, OSM-LIF
• STAT4 Transcription Factor
• STAT4 protein, human

Topics

• Arthritis, Rheumatoid (immunology)
• Autocrine Communication (immunology)
• Cells, Cultured
• Cytokines (biosynthesis)
• Fibroblasts (immunology)
• Gene Expression Profiling
• Gene Expression Regulation (immunology)
• Humans
• Inflammation (immunology)
• Interleukin-6 (immunology)
• Leukemia Inhibitory Factor (immunology)
• Receptors, OSM-LIF (immunology)
• STAT4 Transcription Factor (immunology)
• Synovial Membrane (immunology)
• Transcriptome