IRAK-M Is a Negative Regulator of Toll-like Receptor Signaling

Kobayashi, Koichi S.; Hernandez, Lorraine D.; Galán, Jorge E.; Janeway, Charles A.; Medzhitov, Ruslan; Flavell, Richard A.

doi:10.1016/s0092-8674(02)00827-9

Cited by 1,236 publications

(1,318 citation statements)

References 53 publications

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“…IRAK-M-deficient cells consistently show hyperproduction of inflammatory cytokines in response to various TLR ligands. 32 Furthermore, a model has been proposed in which IRAK-M prevents the dissociation of IRAK4 and IRAK1 from MyD88. 32 Production of inflammatory cytokines in response to various TLR ligands is ablated in IRAK4-deficient mice.…”

Section: Activation Of Nf-jb and Ap-1 By The Myd88-dependent Pathwaymentioning

confidence: 99%

“…32 Furthermore, a model has been proposed in which IRAK-M prevents the dissociation of IRAK4 and IRAK1 from MyD88. 32 Production of inflammatory cytokines in response to various TLR ligands is ablated in IRAK4-deficient mice. 33 Furthermore, IRAK4 mutations are reported in patients with recurrent infections and poor inflammatory responses.…”

Section: Activation Of Nf-jb and Ap-1 By The Myd88-dependent Pathwaymentioning

confidence: 99%

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TLR signaling

2006

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The Toll-like receptor (TLR) family plays an instructive role in innate immune responses against microbial pathogens, as well as the subsequent induction of adaptive immune responses. TLRs recognize specific molecular patterns found in a broad range of microbial pathogens such as bacteria and viruses, triggering inflammatory and antiviral responses and dendritic cell maturation, which result in the eradication of invading pathogens. Individual TLRs interact with different combinations of adapter proteins and activate various transcription factors such as nuclear factor (NF)-jB, activating protein-1 and interferon regulatory factors, driving a specific immune response. This review outlines the recent advances in our understanding of TLR-signaling pathways and their roles in immune responses. Further, we also discuss a new concept of TLR-independent mechanisms for recognition of microbial pathogens.

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Section: Activation Of Nf-jb and Ap-1 By The Myd88-dependent Pathwaymentioning

confidence: 99%

Section: Activation Of Nf-jb and Ap-1 By The Myd88-dependent Pathwaymentioning

confidence: 99%

TLR signaling

2006

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“…In a number of instances, the target of these regulatory mechanisms is the IRAK family of proteins. For example, IRAK-M (IRAK3) inhibits signaling to TRAF6 by fixing IRAK-1/4 to the TLR/MyD88 signaling complex; irakm À/À knockouts exhibit enhanced signaling to NF-kB (Kobayashi et al, 2002). Tollip, an adapter protein constitutively associated with IRAK, is phosphorylated and dissociates following IRAK4 activation (Burns et al, 2000;Zhang and Ghosh, 2002).…”

Section: Toll-like Receptorsmentioning

confidence: 99%

NF-κB and the immune response

2006

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“…However, while much is known about the transduction of TLR4-dependent signals and in particular about the activation of NF-jB, mechanisms that control and down-regulate this critical signal cascade are only poorly defined. Dominant-negative forms of IRAK (IRAK-M [18]) or myeloid differentiation factor 88 (Myd88s) exist that inhibit the dissociation or formation of IRAK/TLR4 complexes and block the initiation of downstream events (reviewed in [2]). More recently, a de-ubiquitinase activity of the cytosolic zinc finger protein A20 has been described that dampens TLR4 signaling by removing ubiquitin residues from the adapter protein TNFR-associated factor-6 [19].…”

Section: Introductionmentioning

confidence: 99%

The zinc finger protein Gfi1 acts upstream of TNF to attenuate endotoxin‐mediated inflammatory responses in the lung

et al. 2006

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Gfi1 is a 55-kD nuclear zinc finger protein that is differentially expressed in lymphoid and myeloid cells. Gfi1 -/-mice show a very strong systemic response to the endotoxin LPS and die rapidly within 36 h with symptoms of septic shock. Here we report that the pathohysiological processes for this exaggerated inflammatory response take place in the lung. After LPS treatment, lungs of Gfi1 -/-mice showed a rapid accumulation of mononuclear cells and a significant overproduction of inflammatory cytokines such as TNF, IL-1b and IL-6. Increased cytokine production was also observed in blood-free perfused lungs from Gfi1 -/-mice exposed to either LPS or overventilation. Alveolar macrophages but not airway epithelial cells from Gfi1 -/-mice were found to be responsible for the enhanced cytokine production. Strikingly, when the TNF gene was deleted, Gfi1 -/-animals were completely rescued from LPS hypersensitivity and had significantly lower IL-1b and IL-6 levels. We conclude that the unrestrained endotoxin response of Gfi1 -/-mice occurs mainly in the lung and that Gfi1 represents a novel factor limiting the inflammatory immune response of this organ, and propose that Gfi1 exerts its regulatory function in alveolar macrophages downstream of the LPS receptor (TLR4) and upstream of TNF.

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IRAK-M Is a Negative Regulator of Toll-like Receptor Signaling

Cited by 1,236 publications

References 53 publications

TLR signaling

TLR signaling

NF-κB and the immune response

The zinc finger protein Gfi1 acts upstream of TNF to attenuate endotoxin‐mediated inflammatory responses in the lung

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