期刊
SCIENCE SIGNALING
卷 9, 期 436, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aac9340
关键词
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资金
- National Medical Research Council (Cooperative Basic Research), Singapore [Grant/0055/2014]
- Singapore Ministry of Education (MOE) Academic Research Council grant [MOE2011-T2-2-012]
- NIH grant [P50-GM107618]
- NIH awards [P41-GM103712, U19-AI068021]
Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) and stimulate the innate immune response through the production of cytokines. The innate immune response depends on the timing of encountering PAMPs, suggesting a short-term memory. In particular, activation of TLR3 appears to prime macrophages for the subsequent activation of TLR7, which leads to synergistically increased production of cytokines. By developing a calibrated mathematical model for the kinetics of TLR3 and TLR7 pathway crosstalk and providing experimental validation, we demonstrated the involvement of the Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in controlling the synergistic production of cytokines. Signaling through this pathway played a dual role: It mediated the synergistic production of cytokines, thus boosting the immune response, and it also maintained homeostasis to avoid an excessive inflammatory response. Thus, we propose that the JAK-STAT pathway provides a cytokine rheostatmechanism, which enablesmacrophages to fine-tune their responses to multiple, temporally separated infection events involving the TLR3 and TLR7 pathways.
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