MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis

Araki, Akihiro; Kanai, Takanori; Ishikura, Takahiro; Makita, Shin; Uraushihara, Koji; Iiyama, Ryoichi; Totsuka, Teruji; Takeda, Kiyoshi; Akira, Shizuo; Watanabe, Mamoru

doi:10.1007/s00535-004-1492-9

Cited by 218 publications

(179 citation statements)

References 44 publications

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“…MyD88 deficiency was shown to prevent colitis in Il-10 -/-as well as NEMO IEC-KO mice [23,31], demonstrating that MyD88 signaling exerts detrimental colitogenic effects in these models. In contrast, Myd88 -/-mice are hypersensitive to DSS-induced colitis [42,43], indicating that MyD88 also serves an essential protective role in the intestine. Being an essential adaptor protein for TLR-induced NF-κB activation, it seems likely that the opposing effects of bacteria-induced MyD88 signaling reflect the colitogenic and protective functions of NF-κB activity in the intestine.…”

Section: Mechanisms Underlying the Dual Role Of Intestinal Nf-κb Actimentioning

confidence: 99%

NF-κB in the regulation of epithelial homeostasis and inflammation

2010

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The IκB kinase/NF-κB signaling pathway has been implicated in the pathogenesis of several inflammatory diseases. Increased activation of NF-κB is often detected in both immune and non-immune cells in tissues affected by chronic inflammation, where it is believed to exert detrimental functions by inducing the expression of proinflammatory mediators that orchestrate and sustain the inflammatory response and cause tissue damage. Thus, increased NF-κB activation is considered an important pathogenic factor in many acute and chronic inflammatory disorders, raising hopes that NF-κB inhibitors could be effective for the treatment of inflammatory diseases. However, ample evidence has accumulated that NF-κB inhibition can also be harmful for the organism, and in some cases trigger the development of inflammation and disease. These findings suggested that NF-κB signaling has important functions for the maintenance of physiological immune homeostasis and for the prevention of inflammatory diseases in many tissues. This beneficial function of NF-κB has been predominantly observed in epithelial cells, indicating that NF-κB signaling has a particularly important role for the maintenance of immune homeostasis in epithelial tissues. It seems therefore that NF-κB displays two faces in chronic inflammation: on the one hand increased and sustained NF-κB activation induces inflammation and tissue damage, but on the other hand inhibition of NF-κB signaling can also disturb immune homeostasis, triggering inflammation and disease. Here, we discuss the mechanisms that control these apparently opposing functions of NF-κB signaling, focusing particularly on the role of NF-κB in the regulation of immune homeostasis and inflammation in the intestine and the skin.

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Section: Mechanisms Underlying the Dual Role Of Intestinal Nf-κb Actimentioning

confidence: 99%

NF-κB in the regulation of epithelial homeostasis and inflammation

2010

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“…Commensal bacteria contribute to tissue protection and repair by stimulating TLRs, which are best known for their essential functions in pathogen detection and protection from infection (8). Mice deficient in TLR2 and TLR4 (which recognize conserved bacterial products such as lipopeptides and LPS) or the TLR signaling adaptor myeloid differentiation factor 88 (MyD88) are phenotypically similar to germfree mice with regard to protection from intestinal injury and subsequent compensatory proliferation (5,7,9,10). Thus perception of injury and induction of tissue repair processes may occur via recognition of commensal microbial products that gain access to the TLRs expressed on myeloid cells upon epithelial barrier disruption (7,11).…”

Section: Innate Immune Recognition Of the Commensal Microflora As A Cmentioning

confidence: 99%

Prostaglandin-secreting cells: a portable first aid kit for tissue repair

Rakoff-Nahoum¹,

Medzhitov²

2007

J. Clin. Invest.

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“…We and others have used an acute model of colitis to address the function of TLR4 in the setting of epithelial injury and inflammation. Administration of DSS to animals genetically deficient in TLR4 or MyD88 results in greater toxicity manifested by increased rectal bleeding, weight loss and mortality compared to wild-type littermates [14][15][16] . We have also found that animals deficient in TLR4 or MyD88 have decreased neutrophil recruitment to the intestine due to defective expression of chemokines and they experience bacterial translocation to mesenteric lymph nodes 15 .…”

Section: Introductionmentioning

confidence: 99%