IL-10 production in macrophages is regulated by a TLR-driven CREB-mediated mechanism that is linked to genes involved in cell metabolism

Sanin, D. E., Prendergast, C. T. and Mountford, A. P. (2015) IL-10 production in macrophages is regulated by a TLR-driven CREB-mediated mechanism that is linked to genes involved in cell metabolism. Journal of Immunology, 195(3), pp. 1218-1232. (doi: 10.4049/jimmunol.1500146) (PMID:26116503) (PMCID:PMC4505959)

Abstract

IL-10 is produced by macrophages in diverse immune settings and is critical in limiting immune-mediated pathology. In helminth infections, macrophages are an important source of IL-10; however, the molecular mechanism underpinning production of IL-10 by these cells is poorly characterized. In this study, bone marrow–derived macrophages exposed to excretory/secretory products released by Schistosoma mansoni cercariae rapidly produce IL-10 as a result of MyD88-mediated activation of MEK/ERK/RSK and p38. The phosphorylation of these kinases was triggered by TLR2 and TLR4 and converged on activation of the transcription factor CREB. Following phosphorylation, CREB is recruited to a novel regulatory element in the Il10 promoter and is also responsible for regulating a network of genes involved in metabolic processes, such as glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation. Moreover, skin-resident tissue macrophages, which encounter S. mansoni excretory/secretory products during infection, are the first monocytes to produce IL-10 in vivo early postinfection with S. mansoni cercariae. The early and rapid release of IL-10 by these cells has the potential to condition the dermal microenvironment encountered by immune cells recruited to this infection site, and we propose a mechanism by which CREB regulates the production of IL-10 by macrophages in the skin, but also has a major effect on their metabolic state.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Prendergast, Dr Catriona
• Authors: Sanin, D. E., Prendergast, C. T., and Mountford, A. P.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Journal of Immunology
• Publisher: American Association of Immunologists
• ISSN: 0022-1767
• ISSN (Online): 1550-6606
• Published Online: 17 July 2015
• Copyright Holders: Copyright © 2015 The Authors
• First Published: First published in Journal of Immunology 195(3):1218-1232
• Publisher Policy: Reproduced under a Creative Commons License