TY - JOUR
T1 - Cooperation between MyD88 and TRIF pathways in TLR synergy via IRF5 activation
AU - Ouyang, Xinshou
AU - Negishi, Hideo
AU - Takeda, Rie
AU - Fujita, Yasuyuki
AU - Taniguchi, Tadatsugu
AU - Honda, Kenya
N1 - Funding Information:
We thank Drs. S. Akira and M. Yamamoto for Myd88 −/− and Trif −/− mice, S. Kondo and T.W. Mak for Irf5 −/− mice, and D. Savitsky for critical reading the manuscript. This work was supported by Kakenhi (Grant-in-Aid for Scientific Research) on Priority Areas “Integrative Research Toward the Conquest of Cancer” and “dynamics of extracellular environments” from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and grants from the Uehara memorial Foundation and the Takeda Science Foundation.
PY - 2007/3/23
Y1 - 2007/3/23
N2 - Signaling by Toll-like receptors (TLRs) is central to evoking innate immunity, wherein each TLR is activated by distinct pathogen-derived agonists. It has been shown previously that TLR signaling occurs in synergy when certain TLR agonist combinations simultaneously activate immune cells. This synergism may constitute a mechanism critical to ensuring the effective activation of the immune system by multiple TLR activating molecules associated with a given pathogen; however, its underlying mechanism(s) remain unclarified. Here, we provide evidence that TLRs utilizing the MyD88 adaptor selectively cooperate with those utilizing the TRIF adaptor for synergistic induction of a set of target genes, and that this synergism is abrogated in cells lacking either MyD88 or TRIF. Moreover, we also provide evidence that this TLR synergy is mediated, at least in part, by activation of the transcription factor interferon regulatory factor 5 (IRF5). Thus, our findings offer a mechanistic insight into TLR synergy, revealing the hitherto unknown cross talk between the MyD88 and TRIF pathways for a robust TLR-mediated activation of the immune system.
AB - Signaling by Toll-like receptors (TLRs) is central to evoking innate immunity, wherein each TLR is activated by distinct pathogen-derived agonists. It has been shown previously that TLR signaling occurs in synergy when certain TLR agonist combinations simultaneously activate immune cells. This synergism may constitute a mechanism critical to ensuring the effective activation of the immune system by multiple TLR activating molecules associated with a given pathogen; however, its underlying mechanism(s) remain unclarified. Here, we provide evidence that TLRs utilizing the MyD88 adaptor selectively cooperate with those utilizing the TRIF adaptor for synergistic induction of a set of target genes, and that this synergism is abrogated in cells lacking either MyD88 or TRIF. Moreover, we also provide evidence that this TLR synergy is mediated, at least in part, by activation of the transcription factor interferon regulatory factor 5 (IRF5). Thus, our findings offer a mechanistic insight into TLR synergy, revealing the hitherto unknown cross talk between the MyD88 and TRIF pathways for a robust TLR-mediated activation of the immune system.
KW - IRF
KW - MyD88
KW - Synergy
KW - TLR
KW - TRIF
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U2 - 10.1016/j.bbrc.2007.01.090
DO - 10.1016/j.bbrc.2007.01.090
M3 - Article
C2 - 17275788
AN - SCOPUS:33846809150
SN - 0006-291X
VL - 354
SP - 1045
EP - 1051
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 4
ER -