Post-transcriptional regulation of adapter molecules by IL-10 inhibits TLR-mediated activation of antigen-presenting cells.
Toll-like receptors (TLRs) act to sense the environment for microbial products and submit danger signals to antigen-presenting cells (APCs) resulting in activation of complex immune responses. In this study, we analyzed the function of human monocyte-derived APCs generated in vitro in the presence of interleukin (IL)-10 upon activation by TLR ligands. Exposure of these APCs to IL-10 resulted in a skewed phenotypic maturation in response to stimuli provided by the TLR ligands, a reduced cytokine production, such as IL-12, IL-6 or tumor necrosis factor-alpha, and impaired capacity to stimulate T-cell activation. Furthermore, CCR7 upregulation in APCs exposed to TLR stimulation as well as migration towards CCL19/MIP-3beta were strongly reduced. IL-10 was found to downregulate MyD88, IRAK1 (IL-1 receptor-associated kinase) and tumor necrosis factor receptor-associated factor 6, essential adaptor molecules for TLR signaling, and to decrease TLR-induced nuclear expression of the nuclear factor-kappaB transcription factors c-Rel and Rel-B as well as interferon regulatory factor (IRF)-3 and IRF-8. This was not due to the inhibition of the mitogen-activated protein kinase pathway, but was rather mediated by the blockage of the PI3K signaling cascade. Interestingly, the inhibition of proteins involved in TLR signaling, such as MyD88, IRAK1 and mammalian target of rapamycin, was due to a selective post-transcriptional regulation.
Knödler
A
A
Department of Oncology, Hematology, Immunology, Rheumatology and Pulmology, University of Tübingen, Tübingen, Germany.
Schmidt
S M
SM
Bringmann
A
A
Weck
M M
MM
Brauer
K M
KM
Holderried
T A W
TA
Heine
A-K
AK
Grünebach
F
F
Brossart
P
P
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D017951:Antigen Presentation / Q000187:drug effects*; D002478:Cells, Cultured / Q000187:drug effects / Q000276:immunology; D054415:Chemokine CCL19 / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000494:pharmacology* / Q000502:physiology; D008024:Ligands; D008213:Lymphocyte Activation; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D010587:Phagocytosis / Q000187:drug effects; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054400:Receptors, CCR7 / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000276:immunology; D051193:Toll-Like Receptors / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C515460:CCL19 protein, human; C515370:CCR7 protein, human; D054415:Chemokine CCL19; D016207:Cytokines; D008024:Ligands; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054400:Receptors, CCR7; D051193:Toll-Like Receptors; D016753:Interleukin-10; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases