The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Kenya Honda - One of the best experts on this subject based on the ideXlab platform.
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essential contribution of irf3 to intestinal homeostasis and microbiota mediated tslp Gene Induction
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Hideo Negishi, Hideyuki Yanai, Shoji Miki, Hana Sarashina, Naoko Taguchiatarashi, Akira Nakajima, Kosuke Matsuki, Nobuyasu Endo, Junko Nishio, Kenya HondaAbstract:The large intestinal epithelial cells and immune cells are exposed to a variety of molecules derived from commensal microbiota that can activate innate receptors, such as Toll-like receptors (TLRs) and retinoic acid-inducible Gene-I-like receptors (RLRs). Although the activation of these receptors is known to be critical for homeostasis of the large intestine, the underlying Gene regulatory mechanisms are not well understood. Here, we show that IFN regulatory factor (IRF)3 is critical for the suppression of dextran sulfate sodium-induced colitis. IRF3-deficient mice exhibited lethal defects in the inflammatory and recovery phases of the colitis, accompanied by marked defects in the Gene Induction for thymic stromal lymphopoietin (TSLP), a cytokine known to be essential for protection of the large intestine. We further provide evidence that DNA and RNA of the large intestinal contents are critical for Tslp Gene Induction via IRF3 activation by cytosolic nucleic acid receptors. We also demonstrate that IRF3 indeed activates the Gene promoter of Tslp via IRF-binding sequences. This newly identified intestinal Gene regulatory mechanism, wherein IRF3 activated by microbiota-derived nucleic acids plays a critical role in intestinal homeostasis, may have clinical implication in colonic inflammatory disorders.
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evidence for licensing of ifn γ induced ifn regulatory factor 1 transcription factor by myd88 in toll like receptor dependent Gene Induction program
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Hideo Negishi, Shinya Sakaguchi, Masahiro Shinohara, Xinshou Ouyang, Hideyuki Yanai, Tadatsugu Taniguchi, Yusuke Ohba, Hiroshi Takayanagi, Yasuyuki Fujita, Kenya HondaAbstract:The recognition of microbial components by Toll-like receptors (TLRs) initiates signal transduction pathways, which trigger the expression of a series of target Genes. It has been reported that TLR signaling is enhanced by cytokines such as IFN-γ, but the mechanisms underlying this enhancement remain unclear. The MyD88 adaptor, which is essential for signaling by many TLRs, recruits members of the IFN regulatory factor (IRF) family of transcription factors, such as IRF5 and IRF7, to evoke the activation of TLR target Genes. In this study we demonstrate that IRF1, which is induced by IFN-γ, also interacts with and is activated by MyD88 upon TLR activation. We provide evidence that MyD88-associated IRF1 migrates into the nucleus more efficiently than non-MyD88-associated IRF1 and that this IRF1 selectively participates in the TLR-dependent Gene Induction program. The critical role of MyD88-dependent “IRF1 licensing” is underscored by the observation that the Induction of a specific Gene subset downstream of the TLR–MyD88 pathway, such as IFN-β, inducible NO synthase, and IL-12p35, are impaired in Irf1-deficient cells. Thus, our present study places IRF1 as an additional member participating in MyD88 signaling and provides a mechanistic insight into the enhancement of the TLR-dependent Gene Induction program by IFN-γ.
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type i inteferon Gene Induction by the interferon regulatory factor family of transcription factors
Immunity, 2006Co-Authors: Kenya Honda, Akinori Takaoka, Tadatsugu TaniguchiAbstract:Summary Induction of type I interferons (IFNs) by viruses and other pathogens is crucial for innate immunity, and it is mediated by the activation of pattern-recognition receptors, such as Toll-like receptors and cytosolic receptors such as RIG-I and MDA5. The type I IFN Induction is primarily controlled at the Gene transcriptional level, wherein a family of transcription factors, interferon regulatory factors (IRFs), plays central roles. Here, we summarize the recent studies on IRFs, providing a paradigm of how Genes are ingeniously regulated during immune responses. We also consider some evolutional aspects on the IFN-IRF system.
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irf family transcription factors in type i interferon Induction
International Congress Series, 2005Co-Authors: Hideyuki Yanai, Kenya Honda, Akinori Takaoka, Tatsuaki Mizutani, Takayuki Inuzuka, Tadatsugu TaniguchiAbstract:Abstract The type I interferon (IFN-α/β) Gene family was identified about a quarter of century ago as the prototype of many cytokine Gene families, and the Gene Induction mechanism for IFN-α/β was extensively studied in the context of host defense against viral infections. More recently, much attention has been focused on the Induction and function of the IFN-α/β system regulated by Toll-like receptors (TLRs), which are critical for linking the innate and adaptive immunities. The understanding of mechanisms underlying IFN-α/β Gene Induction by TLRs is therefore an emerging theme, for which new insights have been gained over the past few years. We summarise recent progress on the role of interferon regulatory factors (IRFs) in the Induction of IFN-α/β Genes in normal cells and plasmacytoid dendritic cells (pDCs) that are specialized to produce IFN-α/β at very high levels upon stimulation by TLR9 and its subfamily members.
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integral role of irf 5 in the Gene Induction programme activated by toll like receptors
Nature, 2005Co-Authors: Akinori Takaoka, Hideo Negishi, Hideyuki Yanai, Yusuke Ohba, Kenya Honda, Seiji Kondo, Gordon S Duncan, Tatsuaki Mizutani, Shin Ichi Kano, Tak W MakAbstract:The activation of Toll-like receptors (TLRs) is central to innate and adaptive immunity. All TLRs use the adaptor MyD88 for signalling, but the mechanisms underlying the MyD88-mediated Gene Induction programme are as yet not fully understood. Here, we demonstrate that the transcription factor IRF-5 is Generally involved downstream of the TLR-MyD88 signalling pathway for Gene Induction of proinflammatory cytokines, such as interleukin-6 (IL-6), IL-12 and tumour-necrosis factor-alpha. In haematopoietic cells from mice deficient in the Irf5 Gene (Irf5-/- mice), the Induction of these cytokines by various TLR ligands is severely impaired, whereas interferon-alpha Induction is normal. We also provide evidence that IRF-5 interacts with and is activated by MyD88 and TRAF6, and that TLR activation results in the nuclear translocation of IRF-5 to activate cytokine Gene transcription. Consistently, Irf5-/- mice show resistance to lethal shock induced by either unmethylated DNA or lipopolysaccharide, which correlates with a marked decrease in the serum levels of proinflammatory cytokines. Thus, our study identifies IRF-5 as a new, principal downstream regulator of the TLR-MyD88 signalling pathway and a potential target of therapeutic intervention to control harmful immune responses.
Tadatsugu Taniguchi - One of the best experts on this subject based on the ideXlab platform.
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evidence for licensing of ifn γ induced ifn regulatory factor 1 transcription factor by myd88 in toll like receptor dependent Gene Induction program
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Hideo Negishi, Shinya Sakaguchi, Masahiro Shinohara, Xinshou Ouyang, Hideyuki Yanai, Tadatsugu Taniguchi, Yusuke Ohba, Hiroshi Takayanagi, Yasuyuki Fujita, Kenya HondaAbstract:The recognition of microbial components by Toll-like receptors (TLRs) initiates signal transduction pathways, which trigger the expression of a series of target Genes. It has been reported that TLR signaling is enhanced by cytokines such as IFN-γ, but the mechanisms underlying this enhancement remain unclear. The MyD88 adaptor, which is essential for signaling by many TLRs, recruits members of the IFN regulatory factor (IRF) family of transcription factors, such as IRF5 and IRF7, to evoke the activation of TLR target Genes. In this study we demonstrate that IRF1, which is induced by IFN-γ, also interacts with and is activated by MyD88 upon TLR activation. We provide evidence that MyD88-associated IRF1 migrates into the nucleus more efficiently than non-MyD88-associated IRF1 and that this IRF1 selectively participates in the TLR-dependent Gene Induction program. The critical role of MyD88-dependent “IRF1 licensing” is underscored by the observation that the Induction of a specific Gene subset downstream of the TLR–MyD88 pathway, such as IFN-β, inducible NO synthase, and IL-12p35, are impaired in Irf1-deficient cells. Thus, our present study places IRF1 as an additional member participating in MyD88 signaling and provides a mechanistic insight into the enhancement of the TLR-dependent Gene Induction program by IFN-γ.
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type i inteferon Gene Induction by the interferon regulatory factor family of transcription factors
Immunity, 2006Co-Authors: Kenya Honda, Akinori Takaoka, Tadatsugu TaniguchiAbstract:Summary Induction of type I interferons (IFNs) by viruses and other pathogens is crucial for innate immunity, and it is mediated by the activation of pattern-recognition receptors, such as Toll-like receptors and cytosolic receptors such as RIG-I and MDA5. The type I IFN Induction is primarily controlled at the Gene transcriptional level, wherein a family of transcription factors, interferon regulatory factors (IRFs), plays central roles. Here, we summarize the recent studies on IRFs, providing a paradigm of how Genes are ingeniously regulated during immune responses. We also consider some evolutional aspects on the IFN-IRF system.
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irf family transcription factors in type i interferon Induction
International Congress Series, 2005Co-Authors: Hideyuki Yanai, Kenya Honda, Akinori Takaoka, Tatsuaki Mizutani, Takayuki Inuzuka, Tadatsugu TaniguchiAbstract:Abstract The type I interferon (IFN-α/β) Gene family was identified about a quarter of century ago as the prototype of many cytokine Gene families, and the Gene Induction mechanism for IFN-α/β was extensively studied in the context of host defense against viral infections. More recently, much attention has been focused on the Induction and function of the IFN-α/β system regulated by Toll-like receptors (TLRs), which are critical for linking the innate and adaptive immunities. The understanding of mechanisms underlying IFN-α/β Gene Induction by TLRs is therefore an emerging theme, for which new insights have been gained over the past few years. We summarise recent progress on the role of interferon regulatory factors (IRFs) in the Induction of IFN-α/β Genes in normal cells and plasmacytoid dendritic cells (pDCs) that are specialized to produce IFN-α/β at very high levels upon stimulation by TLR9 and its subfamily members.
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Gene Induction pathways mediated by distinct irfs during viral infection
Biochemical and Biophysical Research Communications, 2001Co-Authors: Takeo Nakaya, Mitsuharu Sato, Naoki Hata, Masataka Asagiri, Hirofumi Suemori, Shigeru Noguchi, Nobuyuki Tanaka, Tadatsugu TaniguchiAbstract:During viral infection, interferon-alpha/beta (IFN-alpha/beta) and many IFN-inducible Genes are induced to elicit antiviral responses of the host. Using cells with a Gene disruption(s) for the IRF family of transcription factors, we provide evidence that these Genes, containing similar IRF-binding cis-elements, are classified into distinct groups, based on the Gene Induction pathway(s). The IFN-beta Gene Induction is dependent on either IRF-3 or IRF-7, whereas Induction of the IFN-alpha Gene family is IRF-7-dependent. On the other hand, ISG15, ISG54 and IP-10 are induced by either IRF-3 or IFN stimulated Gene factor 3 (ISGF3). We also show that another group of Genes is totally dependent on ISGF3. Thus, during viral infection, a given Gene responds either directly to a virus or virus-induced IFN-alpha/beta or both through distinct pathways. The differential utilization of these Induction pathways for these Genes during viral infection may reflect their distinct functional roles in the efficient antiviral response.
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critical role of the interleukin 2 il 2 receptor gamma chain associated jak3 in the il 2 induced c fos and c myc but not bcl 2 Gene Induction
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Atsuo Kawahara, Yasuhiro Minami, Tadaaki Miyazaki, James N Ihle, Tadatsugu TaniguchiAbstract:The interleukin 2 receptor (IL-2R) consists of three subunits, the IL-2R alpha, IL-2R beta c, and IL-2R gamma c chains. Two Janus family protein tyrosine kinases (PTKs), Jak1 and Jak3, were shown to associate with IL-2R beta c and IL-2R gamma c, respectively, and their PTK activities are increased after IL-2 stimulation. A Jak3 mutant with truncation of the C-terminal PTK domain lacks its intrinsic kinase activity but can still associate with IL-2R gamma c. In a hematopoietic cell line, F7, that responds to either IL-2 or IL-3, overexpression of this Jak3 mutant results in selective inhibition of the IL-2-induced activation of Jak1/Jak3 PTKs and of cell proliferation. Of the three target nuclear protooncoGenes of the IL-2 signaling, c-fos and c-myc Genes, but not the bcl-2 Gene, were found to be impaired. On the other hand, overexpression of the dominant negative form of the IL-2R gamma c chain, which lacks most of its cytoplasmic domain, in F7 cells resulted in the inhibition of all three protooncoGenes. These results provide a further molecular basis for the critical role of Jak3 in IL-2 signaling and also suggest a Jak PTK-independent signaling pathway(s) for the bcl-2 Gene Induction by IL-2R.
Anthony M Brown - One of the best experts on this subject based on the ideXlab platform.
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measurement of cytochrome p450 Gene Induction in human hepatocytes using quantitative real time reverse transcriptase polymerase chain reaction
Drug Metabolism and Disposition, 2000Co-Authors: Wayne P Bowen, Jae E Carey, Asik Miah, Heather F Mcmurray, Peter W Munday, Rowena S James, Robert A Coleman, Anthony M BrownAbstract:Drug-induced changes in expression of cytochrome (CYP) P450 Genes are a key cause of drug-drug interactions. Consequently, preclinical prediction of these changes by novel compounds is an integral component of drug development. To date, in vitro models of CYP Induction have used mRNA measurement, immunodetection, and substrate metabolism as reporters. Here, we describe the application of quantitative real-time reverse transcriptase polymerase chain reaction to study CYP1A1 and CYP3A4 Gene Induction in 5-day-old cultures of human hepatocytes by known CYP inducers. After 5 days in culture, CYP1A1 expression was significantly elevated (5.1- to 26-fold; P <.01) in all four livers studied. In direct contrast, CYP3A4 mRNA levels consistently decreased during culture (80- to 300-fold; P <.001). In three independent experiments, a 48-h exposure to 3-methylcholanthrene, omeprazole, and lansoprazole significantly induced CYP1A1 expression in comparison to untreated cultures (P <.05). Rifampicin and solvent were without effect on CYP1A1 expression. Under identical experimental conditions, rifampicin and lansoprazole significantly elevated CYP3A4 mRNA expression (P <.05), whereas 3-methylcholanthrene, omeprazole, and dimethyl sulfoxide were without significant effect. These data demonstrate the applicability of quantitative reverse transcriptase polymerase chain reaction to the determination of Gene dynamics in human hepatocytes. This offers a highly specific alternative to quantification of drug effects on CYP expression using immunodetection and substrate metabolism.
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measurement of cytochrome p450 Gene Induction in human hepatocytes using quantitative real time reverse transcriptase polymerase chain reaction
Drug Metabolism and Disposition, 2000Co-Authors: Wayne P Bowen, Jae E Carey, Asik Miah, Heather F Mcmurray, Peter W Munday, Rowena S James, Robert A Coleman, Anthony M BrownAbstract:Drug-induced changes in expression of cytochrome (CYP) P450 Genes are a key cause of drug-drug interactions. Consequently, preclinical prediction of these changes by novel compounds is an integral component of drug development. To date, in vitro models of CYP Induction have used mRNA measurement, immunodetection, and substrate metabolism as reporters. Here, we describe the application of quantitative real-time reverse transcriptase polymerase chain reaction to studyCYP1A1 and CYP3A4 Gene Induction in 5-day-old cultures of human hepatocytes by known CYP inducers. After 5 days in culture, CYP1A1 expression was significantly elevated (5.1- to 26-fold; P
Wayne P Bowen - One of the best experts on this subject based on the ideXlab platform.
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measurement of cytochrome p450 Gene Induction in human hepatocytes using quantitative real time reverse transcriptase polymerase chain reaction
Drug Metabolism and Disposition, 2000Co-Authors: Wayne P Bowen, Jae E Carey, Asik Miah, Heather F Mcmurray, Peter W Munday, Rowena S James, Robert A Coleman, Anthony M BrownAbstract:Drug-induced changes in expression of cytochrome (CYP) P450 Genes are a key cause of drug-drug interactions. Consequently, preclinical prediction of these changes by novel compounds is an integral component of drug development. To date, in vitro models of CYP Induction have used mRNA measurement, immunodetection, and substrate metabolism as reporters. Here, we describe the application of quantitative real-time reverse transcriptase polymerase chain reaction to study CYP1A1 and CYP3A4 Gene Induction in 5-day-old cultures of human hepatocytes by known CYP inducers. After 5 days in culture, CYP1A1 expression was significantly elevated (5.1- to 26-fold; P <.01) in all four livers studied. In direct contrast, CYP3A4 mRNA levels consistently decreased during culture (80- to 300-fold; P <.001). In three independent experiments, a 48-h exposure to 3-methylcholanthrene, omeprazole, and lansoprazole significantly induced CYP1A1 expression in comparison to untreated cultures (P <.05). Rifampicin and solvent were without effect on CYP1A1 expression. Under identical experimental conditions, rifampicin and lansoprazole significantly elevated CYP3A4 mRNA expression (P <.05), whereas 3-methylcholanthrene, omeprazole, and dimethyl sulfoxide were without significant effect. These data demonstrate the applicability of quantitative reverse transcriptase polymerase chain reaction to the determination of Gene dynamics in human hepatocytes. This offers a highly specific alternative to quantification of drug effects on CYP expression using immunodetection and substrate metabolism.
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measurement of cytochrome p450 Gene Induction in human hepatocytes using quantitative real time reverse transcriptase polymerase chain reaction
Drug Metabolism and Disposition, 2000Co-Authors: Wayne P Bowen, Jae E Carey, Asik Miah, Heather F Mcmurray, Peter W Munday, Rowena S James, Robert A Coleman, Anthony M BrownAbstract:Drug-induced changes in expression of cytochrome (CYP) P450 Genes are a key cause of drug-drug interactions. Consequently, preclinical prediction of these changes by novel compounds is an integral component of drug development. To date, in vitro models of CYP Induction have used mRNA measurement, immunodetection, and substrate metabolism as reporters. Here, we describe the application of quantitative real-time reverse transcriptase polymerase chain reaction to studyCYP1A1 and CYP3A4 Gene Induction in 5-day-old cultures of human hepatocytes by known CYP inducers. After 5 days in culture, CYP1A1 expression was significantly elevated (5.1- to 26-fold; P
Hideo Negishi - One of the best experts on this subject based on the ideXlab platform.
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essential contribution of irf3 to intestinal homeostasis and microbiota mediated tslp Gene Induction
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Hideo Negishi, Hideyuki Yanai, Shoji Miki, Hana Sarashina, Naoko Taguchiatarashi, Akira Nakajima, Kosuke Matsuki, Nobuyasu Endo, Junko Nishio, Kenya HondaAbstract:The large intestinal epithelial cells and immune cells are exposed to a variety of molecules derived from commensal microbiota that can activate innate receptors, such as Toll-like receptors (TLRs) and retinoic acid-inducible Gene-I-like receptors (RLRs). Although the activation of these receptors is known to be critical for homeostasis of the large intestine, the underlying Gene regulatory mechanisms are not well understood. Here, we show that IFN regulatory factor (IRF)3 is critical for the suppression of dextran sulfate sodium-induced colitis. IRF3-deficient mice exhibited lethal defects in the inflammatory and recovery phases of the colitis, accompanied by marked defects in the Gene Induction for thymic stromal lymphopoietin (TSLP), a cytokine known to be essential for protection of the large intestine. We further provide evidence that DNA and RNA of the large intestinal contents are critical for Tslp Gene Induction via IRF3 activation by cytosolic nucleic acid receptors. We also demonstrate that IRF3 indeed activates the Gene promoter of Tslp via IRF-binding sequences. This newly identified intestinal Gene regulatory mechanism, wherein IRF3 activated by microbiota-derived nucleic acids plays a critical role in intestinal homeostasis, may have clinical implication in colonic inflammatory disorders.
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evidence for licensing of ifn γ induced ifn regulatory factor 1 transcription factor by myd88 in toll like receptor dependent Gene Induction program
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Hideo Negishi, Shinya Sakaguchi, Masahiro Shinohara, Xinshou Ouyang, Hideyuki Yanai, Tadatsugu Taniguchi, Yusuke Ohba, Hiroshi Takayanagi, Yasuyuki Fujita, Kenya HondaAbstract:The recognition of microbial components by Toll-like receptors (TLRs) initiates signal transduction pathways, which trigger the expression of a series of target Genes. It has been reported that TLR signaling is enhanced by cytokines such as IFN-γ, but the mechanisms underlying this enhancement remain unclear. The MyD88 adaptor, which is essential for signaling by many TLRs, recruits members of the IFN regulatory factor (IRF) family of transcription factors, such as IRF5 and IRF7, to evoke the activation of TLR target Genes. In this study we demonstrate that IRF1, which is induced by IFN-γ, also interacts with and is activated by MyD88 upon TLR activation. We provide evidence that MyD88-associated IRF1 migrates into the nucleus more efficiently than non-MyD88-associated IRF1 and that this IRF1 selectively participates in the TLR-dependent Gene Induction program. The critical role of MyD88-dependent “IRF1 licensing” is underscored by the observation that the Induction of a specific Gene subset downstream of the TLR–MyD88 pathway, such as IFN-β, inducible NO synthase, and IL-12p35, are impaired in Irf1-deficient cells. Thus, our present study places IRF1 as an additional member participating in MyD88 signaling and provides a mechanistic insight into the enhancement of the TLR-dependent Gene Induction program by IFN-γ.
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integral role of irf 5 in the Gene Induction programme activated by toll like receptors
Nature, 2005Co-Authors: Akinori Takaoka, Hideo Negishi, Hideyuki Yanai, Yusuke Ohba, Kenya Honda, Seiji Kondo, Gordon S Duncan, Tatsuaki Mizutani, Shin Ichi Kano, Tak W MakAbstract:The activation of Toll-like receptors (TLRs) is central to innate and adaptive immunity. All TLRs use the adaptor MyD88 for signalling, but the mechanisms underlying the MyD88-mediated Gene Induction programme are as yet not fully understood. Here, we demonstrate that the transcription factor IRF-5 is Generally involved downstream of the TLR-MyD88 signalling pathway for Gene Induction of proinflammatory cytokines, such as interleukin-6 (IL-6), IL-12 and tumour-necrosis factor-alpha. In haematopoietic cells from mice deficient in the Irf5 Gene (Irf5-/- mice), the Induction of these cytokines by various TLR ligands is severely impaired, whereas interferon-alpha Induction is normal. We also provide evidence that IRF-5 interacts with and is activated by MyD88 and TRAF6, and that TLR activation results in the nuclear translocation of IRF-5 to activate cytokine Gene transcription. Consistently, Irf5-/- mice show resistance to lethal shock induced by either unmethylated DNA or lipopolysaccharide, which correlates with a marked decrease in the serum levels of proinflammatory cytokines. Thus, our study identifies IRF-5 as a new, principal downstream regulator of the TLR-MyD88 signalling pathway and a potential target of therapeutic intervention to control harmful immune responses.
