Differential post-transcriptional regulation of IL-10 by TLR2 and TLR4-activated macrophages.
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 mRNA. TLR2 signals promoted a rapid induction and degradation of Il10 mRNA, 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.
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
Maria
M
Teixeira-Coelho
Joana
J
Guedes
Pedro
P
Ferreirinha
Ashleigh
A
Howes
Jorge
J
Pedrosa
Fernando
F
Rodrigues
Wi S
WS
Lai
Perry J
PJ
Blackshear
Anne
A
O'Garra
António G
AG
Castro
Margarida
M
Saraiva
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D001419:Bacteria / Q000276:immunology; D004789:Enzyme Activation; D005260:Female; D005786:Gene Expression Regulation; D016753:Interleukin-10 / Q000235:genetics*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D051816:Tristetraprolin / Q000172:deficiency; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; D016753:Interleukin-10; D012333:RNA, Messenger; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051816:Tristetraprolin; D048051:p38 Mitogen-Activated Protein Kinases; C476286:Ticam1 protein, mouse
IL-10; MAPKs; Post-transcriptional regulation; TLRs