Targeted Disruption of the MyD88 Gene Results in Loss of IL-1- and IL-18-Mediated Function

Adachi, Osamu; Kawai, Taro; Takeda, Kiyoshi; Matsumoto, Makoto; Tsutsui, Hiroko; Sakagami, Masafumi; Nakanishi, Kenji; Akira, Shizuo

doi:10.1016/s1074-7613(00)80596-8

Cited by 1,885 publications

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“…In myeloid cells, the LPS/LPS-binding protein complex binds CD14 and MD-2 [4,5] and the subsequent dimerisation of TLR4 recruits IL-1R-associated serine kinase-4 (IRAK-4) via the adaptors myeloid differentiation protein 88 (MyD88) and TIR domain-containing adaptor protein (TIRAP) [29,30]. As a consequence, systemic LPS responses are severely decreased in Myd88 -/-, Irak -/-and Tirap -/-mice [29,31,32].…”

Section: Resultsmentioning

confidence: 99%

“…Tlr4 -/- [45], Tlr2 -/- [46], Myd88 -/- [30] and Tirap -/- [29] mice were generated in the C57BL/6 mouse background, and Trif -/- [47] and Tram -/-[48] mice were generated in the C57BL/6/129 mouse background and were made in the BIKEN animal facilities (Osaka, Japan). Lps2, a non-functional codominant allele of Trif, was induced by N-ethyl-N-nitrosourea mutagenesis on a pure C57BL/6 mouse background [49] in the Scripps Institute animal facilities (La Jolla CA).…”

Section: Mouse Strainsmentioning

confidence: 99%

“…1). The results showed that P fimbriated E. coli trigger a TLR4-dependent response in vivo in the urinary tract and that the urinary tract mucosa remains inert when exposed to a non-adhesive strain, or when TLR4 is inactivated.Involvement of Trif Lps2/Lps2 /Tram in the response to P fimbriated E. coliIn myeloid cells, the LPS/LPS-binding protein complex binds 5] and the subsequent dimerisation of TLR4 recruits IL-1R-associated serine kinase-4 (IRAK-4) via the adaptors myeloid differentiation protein 88 (MyD88) and TIR domain-containing adaptor protein (TIRAP) [29,30]. As a consequence, systemic LPS responses are severely decreased in Myd88 -/-, Irak -/-and Tirap -/-mice [29,31,32].…”

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Mechanism of pathogen‐specific TLR4 activation in the mucosa: Fimbriae, recognition receptors and adaptor protein selection

et al. 2006

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The mucosal host defence discriminates pathogens from commensals, and prevents infection while allowing the normal flora to persist. Paradoxically, Toll-like receptors (TLR) control the mucosal defence against pathogens, even though the TLR recognise conserved molecules like LPS, which are shared between pathogens and commensals. This study proposes a mechanism of pathogen-specific mucosal TLR4 activation, involving adhesive ligands and their host cell receptors. TLR4 signalling was activated in CD14-negative, LPS-unresponsive epithelial cells by P fimbriated, uropathogenic Escherichia coli but not by a mutant lacking fimbriae. Epithelial TLR4 signalling in vivo involved the glycosphingolipid receptors for P fimbriae and the adaptor proteins Toll/IL-1R (TIR) domain-containing adaptor inducing IFN-b (TRIF)/TRIF-related adaptor molecule (TRAM), but myeloid differentiation protein 88 (MyD88)/TIR domain-containing adaptor protein were not required for the epithelial response. Substituting the P fimbriae with type 1 fimbriae changed TLR4 signalling from the TRIF to the MyD88 adaptor pathway. In addition, the adaptor proteins and the fimbrial type were found to influence bacterial clearance. Trif -/-and Tram -/-mice remained infected with P fimbriated E. coli but cleared thetype 1 fimbriated strain, while Myd88 -/-mice became carriers of both the P and the type 1 fimbriated bacteria. Thus, TLR4 may be engaged specifically by pathogens, when the proper cell surface receptors are engaged by virulence ligands. IntroductionToll-like receptors (TLR) control the innate host defence at mucosal surfaces and yet commensals do not induce an inflammatory response at those sites. The relative inertia to the commensals is paradoxical, as the TLR recognise conserved pathogen-associated molecular patterns (PAMP), which are present on both pathogenic and commensal bacteria. Lipolysaccharide (LPS), flagellin, peptidoglycan or DNA may bind directly to the TLR but in addition, co-receptors are needed to enhance the TLR response to these conserved ligands [1][2][3]. Myeloid cells use CD14 and MD-2 as co-receptors for LPS in TLR4 signalling, and minute amounts of LPS may elicit a strong systemic inflammatory response [4,5]. However, the TLR response to pathogen attack at mucosal surfaces is controlled by different interactions. Epithelial cells must be protected from constant TLR activation by commensals and their PAMP, in order for mucosal integrity to be maintained. The epithelial cells thus lack co-receptors like CD14 [6][7][8][9][10][11], and in addition, commensals have been suggested to actively suppress epithelia responses through NF-jB [12,13]. Yet, mucosal pathogens evoke rapid TLR4-dependent responses at mucosal sites, suggesting that alternative ligands and receptors might be involved in mucosal TLR activation. Pathogens use adhesive surface ligands to break the inertia of the mucosal barrier [14][15][16]. The innate defence is activated as a direct result of these interactions and epithelial cells produce the first wave of me...

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Section: Resultsmentioning

confidence: 99%

Section: Mouse Strainsmentioning

confidence: 99%

mentioning

confidence: 99%

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Mechanism of pathogen‐specific TLR4 activation in the mucosa: Fimbriae, recognition receptors and adaptor protein selection

et al. 2006

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“…Female 4-6-wk-old BALB/c, C57BL/6, WBB6F1-1/1, and mast celldeficient WBB6F1-W/W v mice were purchased from Japan SLC (Tokyo, Japan), Stat6-deficient mice [28] on BALB/c background were provided by Dr. Hiroshi Nakajima (Chiba University, Chiba, Japan), Myd88-deficient mice [29] on C57BL/6 background were purchased from Oriental Yeast (Tokyo, Japan), and these mice were bred under specific pathogen-free conditions. All animal experiments were approved by the Institutional Review Board of the University of Yamanashi.…”

Section: Micementioning

confidence: 99%

Thymic stromal lymphopoietin is a critical mediator of IL‐13‐driven allergic inflammation

et al. 2009

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Both thymic stromal lymphopoietin (TSLP) and IL-13 are essential cytokines for the development of allergic inflammation. However, a causal link between TSLP and IL- 13 has not yet been fully elucidated. This study aimed to investigate whether IL-13 induces TSLP expression and whether the induction contributes to the development of allergic inflammation. We found that IL-13 induced TSLP expression in mouse nasal tissue specimens in a Stat6-dependent manner. In addition, intranasal challenge of mice with IL-13 induced TSLP expression in the nasal epithelium. Importantly, intranasal IL-13 challenge induced eosinophilia and goblet cell hyperplasia in the nasal mucosa in mice, which was inhibited by the blockade of TSLP activity with anti-TSLP Ab. These findings suggest that TSLP is an important mediator of IL-13-driven allergic inflammation in the nasal mucosa. Taken together with the recent findings that IL-13 is a critical downstream element for TSLP-driven allergic inflammation, TSLP may function both upstream and downstream of IL-13, thus providing an additional rationale as to why TSLP plays such a central role in the development of allergic inflammation.Key words: Allergic inflammation . Epithelial cells . IL-13 . Thymic stromal lymphopoietin Supporting Information available online IntroductionThymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine, which binds to a TSLP receptor (TSLPR) consisting of the IL-7 receptor a-chain and a common g receptor-like chain [1,2]. TSLP was originally identified as a factor derived from a thymic stromal cell line that could support the growth of a mouse B-cell line [3].However, recent evidence has demonstrated TSLP, derived from epithelial cells, to be a critical factor for allergic inflammation [1,2,4]. For instance, transgenic mice expressing TSLP in keratinocytes or in lung epithelial cells develop atopic dermatitisor asthma-like inflammation in the skin or the lung, respectively, while TSLPR-deficient mice fail to develop an inflammatory lung response to inhaled antigen [5][6][7].IL-13, a Th2-type cytokine, is a central mediator for allergic inflammation [8,9]. The blockade of IL-13 markedly inhibits allergen-induced airway hyperresponsiveness, mucus production, and eosinophilia whereas IL-13 delivery to the airway causes SHORT COMMUNICATION 3078these effects in mice [8][9][10][11]. Therefore, IL-13 as well as TSLP is necessary and sufficient for the development of allergic inflammation. However, the relationship between TSLP and IL-13 in allergic inflammation has not yet been fully elucidated.This study thus investigated the causal link between IL-13 and TSLP in allergic inflammation. For this purpose, we examined the effects of IL-13 on TSLP expression both in vitro and in vivo using mouse nasal tissue explants and a mouse model of allergic inflammation in the nasal mucosa, respectively. The current results suggest that TSLP is induced by IL-13 and is critical for the development of IL-13-driven allergic inflammation. Because recent studies suggest that TSLP-dri...

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“…1,2 It is also thought to activate NK cells 3,4 and monocytes, including the myelomonocytic cell line KG-1. 5-10 IL18 signal transduction is mediated via a heterodimeric receptor 11 that engages IRAK via Myd88 [12][13][14] leading to activation of the NFkB pathway 1,15 via NIK, as well as the activation of AP1 via JNK. 13 Whether IL18 receptor engagement activates other pathways, is not known.…”

Section: Introductionmentioning

confidence: 99%

cis-Element clustering correlates with dose-dependent pro- and antisignaling effects of IL18

et al. 2004

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We examine the effects of IL18 on monocytes by performing microarray experiments using cell line KG1. Based on sensitivity to IL18, we identified three functionally distinct gene expression clusters (EC). We see little proinflammatory gene induction at low IL18 concentrations, but instead observe induction of diverse NFkB signaling inhibitors. Conversely, intermediate concentrations of IL18 induced proinflammatory genes including the activating subunits of NFkB. At the highest IL18 concentration, we observe a third gene cluster containing the proapoptotic Fas gene among others. Clustering of IL18-responsive genes based on cis-elements in their promoters agreed well with the ECs. We conclude that IL18 produces a dosedependent transcriptional response that can in part be attributed to the composition of cis-elements in the promoters of IL18-responsive genes. These results also support a model for regulatory mechanisms that prevent spurious immune response due to weak cytokine fluctuations and a separate mechanism enabling induction of proinflammatory functions by higher levels of cytokine.

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Targeted Disruption of the MyD88 Gene Results in Loss of IL-1- and IL-18-Mediated Function

Cited by 1,885 publications

References 48 publications

Mechanism of pathogen‐specific TLR4 activation in the mucosa: Fimbriae, recognition receptors and adaptor protein selection

Mechanism of pathogen‐specific TLR4 activation in the mucosa: Fimbriae, recognition receptors and adaptor protein selection

Thymic stromal lymphopoietin is a critical mediator of IL‐13‐driven allergic inflammation

cis-Element clustering correlates with dose-dependent pro- and antisignaling effects of IL18

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