PAFR activation of NF-κB p65 or p105 precursor dictates pro- and anti-inflammatory responses during TLR activation in murine macrophages

Ishizuka, E. K., Filgueiras, L. R., Rios, F. J. , Serezani, C. H. and Jancar, S. (2016) PAFR activation of NF-κB p65 or p105 precursor dictates pro- and anti-inflammatory responses during TLR activation in murine macrophages. Scientific Reports, 6, 32092. (doi: 10.1038/srep32092) (PMID:27554194) (PMCID:PMC4995467)

Abstract

Platelet-activating factor receptor (PAFR) is a G protein-coupled receptor (GPCR) implicated in many diseases. Toll-like receptors (TLRs) play a critical role in shaping innate and adaptive immune responses. In this study, we investigated whether PAFR signaling changes the macrophages responsiveness to agonists of TLR2 (Pam3Cys), TLR4 (LPS), and TLR3 agonist Poly(I:C). Exogenous PAF inhibited the production of pro-inflammatory cytokines (IL-12p40, IL-6, and TNF-α) and increased anti-inflammatory IL-10 in macrophages challenged with Pam3Cys and LPS, but not with Poly (I:C). PAF did not affect mRNA expression of MyD88, suggesting that PAF acts downstream the adaptor. PAF inhibited LPS-induced phosphorylation of NF-κB p65 and increased NF-κB p105 phosphorylation, which is processed in the proteasome to generate p50 subunit. The PAF potentiation of IL-10 production was dependent on proteasome processing but independent of NF-κB transactivation domain. Inhibition of p50 abolished the PAF-induced IL-10 production. These findings indicate that the impaired transcriptional activity of the p65 subunit and the enhanced p105 phosphorylation induced by PAF are responsible for down regulation of pro-inflammatory cytokines and up regulation of IL-10, respectively, in LPS-challenged macrophages. Together, our data unveil a heretofore unrecognized role for PAFR in modulating activation of NF-κB in macrophages.

• Item Type: Articles
• Additional Information: This work was supported by National Institutes of Health Grants, HL-103777–01 and HL-124159-01 (C. H. S.), Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) and and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Rios, Dr Francisco
• Authors: Ishizuka, E. K., Filgueiras, L. R., Rios, F. J., Serezani, C. H., and Jancar, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Scientific Reports
• Publisher: Nature Research
• ISSN: 2045-2322
• ISSN (Online): 2045-2322
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Scientific Reports 6: 32092
• Publisher Policy: Reproduced under a Creative Commons License