1. Differential post-transcriptional regulation of IL-10 by TLR2 and TLR4-activated macrophages.
- Author
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Teixeira‐Coelho, Maria, Guedes, Joana, Ferreirinha, Pedro, Howes, Ashleigh, Pedrosa, Jorge, Rodrigues, Fernando, Lai, Wi S., Blackshear, Perry J., O'Garra, Anne, Castro, António G., and Saraiva, Margarida
- Abstract
The activation of TLRs by microbial molecules triggers intracellular-signaling cascades and the expression of cytokines such as IL-10. Il10 expression is tightly controlled to ensure effective immune responses, while preventing pathology. Maximal TLR-induction of Il10 transcription in macrophages requires signaling through the MAPKs, ERK, and p38. Signals via p38 downstream of TLR4 activation also regulate IL-10 at the post-transcriptional level, but whether this mechanism operates downstream of other TLRs is not clear. We compared the regulation of IL-10 production in TLR2 and TLR4-stimulated BM-derived macrophages and found different stability profiles for the Il10 m RNA. TLR2 signals promoted a rapid induction and degradation of Il10 m RNA, whereas TLR4 signals protected Il10 mRNA from rapid degradation, due to the activation of Toll/ IL-1 receptor domain-containing adaptor inducing IFN-β ( TRIF) and enhanced p38 signaling. This differential post-transcriptional mechanism contributes to a stronger induction of IL-10 secretion via TLR4. Our study provides a molecular mechanism for the differential IL-10 production by TLR2- or TLR4-stimulated BMMs, showing that p38-induced stability is not common to all TLR-signaling pathways. This mechanism is also observed upon bacterial activation of TLR2 or TLR4 in BMMs, contributing to IL-10 modulation in these cells in an infection setting. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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