IL-1 receptor-associated kinase M downregulates DSS-induced colitis†

Berglund, Martin; Melgar, Silvia; Kobayashi, Koichi S.; Hörnquist, Elisabeth Hultgren; Hultgren, Olof

doi:10.1002/ibd.21287

Cited by 27 publications

(30 citation statements)

References 52 publications

(56 reference statements)

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“…Prior studies have evaluated Irak-m −/− mice in both dextran sulfate sodium (DSS) and Il10 −/− colitis models (Berglund et al, 2010, Biswas et al, 2011). These prior studies revealed that IRAK-M functions to attenuate the progression of experimental colitis (Berglund et al, 2010, Biswas et al, 2011). Here we utilized Irak-m −/− mice in an acute colitis model induced with 5% DSS (Okayasu et al, 1990).…”

Section: Resultsmentioning

confidence: 99%

Enhanced Mucosal Defense and Reduced Tumor Burden in Mice with the Compromised Negative Regulator IRAK-M

et al. 2017

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Aberrant inflammation is a hallmark of inflammatory bowel disease (IBD) and colorectal cancer. IRAK-M is a critical negative regulator of TLR signaling and overzealous inflammation. Here we utilize data from human studies and Irak-m−/− mice to elucidate the role of IRAK-M in the modulation of gastrointestinal immune system homeostasis. In human patients, IRAK-M expression is up-regulated during IBD and colorectal cancer. Further functional studies in mice revealed that Irak-m−/− animals are protected against colitis and colitis associated tumorigenesis. Mechanistically, our data revealed that the gastrointestinal immune system of Irak-m−/− mice is highly efficient at eliminating microbial translocation following epithelial barrier damage. This attenuation of pathogenesis is associated with expanded areas of gastrointestinal associated lymphoid tissue (GALT), increased neutrophil migration, and enhanced T-cell recruitment. Further evaluation of Irak-m−/− mice revealed a splice variant that robustly activates NF-κB signaling. Together, these data identify IRAK-M as a potential target for future therapeutic intervention.

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Section: Resultsmentioning

confidence: 99%

Enhanced Mucosal Defense and Reduced Tumor Burden in Mice with the Compromised Negative Regulator IRAK-M

et al. 2017

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“…Multiple mechanisms of negative regulation operate at different levels of the pathway to prevent over-activation of TLRs signaling. Intracellularly, the TLR signaling pathway can be regulated by cytoplasmatic molecules, such as MyD88s, IRAK-M, TOLLIP, and by activation of the PI3K/Akt pathway, among others (Arancibia et al 2011;Berglund et al 2010;Burns et al 2003;Kobayashi et al 2002;Zhang and Ghosh 2002). Extracellularly, soluble TLR (sTLR) behaves as a decoy receptor that counteracts receptor activation.…”

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confidence: 99%

Increased production of soluble TLR2 by lamina propria mononuclear cells from ulcerative colitis patients

et al. 2012

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“…SIGIRR knockout mice have normal susceptibility to systemic LPS toxicity but hyper-susceptibility to intestinal inflammation [94, 95], suggesting an intestinal specific role of SIGIRR in intestinal inflammation. IRAK-M is a negative regulator of TLR signaling [84], and IRAK-M is shown to down-regulate dextran sulfate sodium-induced colitis [96]. The colonic epithelial cells from ulcerative colitis patients express lower levels of PPARγ [85], while PPARγ ligand suppresses LPS-induced NF-κB promoter activity and dampens the inflammation in intestinal epithelial cells [97].…”

Section: Negative Regulators Of Tlr Signalingmentioning

confidence: 99%

Toll-like receptor regulation of intestinal development and inflammation in the pathogenesis of necrotizing enterocolitis

2014

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Toll-like receptors (TLRs) are a structurally related family of molecules that respond to a wide variety of endogenous and exogenous ligands, and which serve as important components of the innate immune system. While TLRs have established roles in host defense, these molecules have also been shown to play important roles in the development of various disease states. A particularly important example of the role of TLRs in disease induction includes necrotizing enterocolitis (NEC), which is the most common gastrointestinal disease in preterm infants, and which is associated with extremely high morbidity and mortality rates. The development of NEC is thought to reflect an abnormal interaction between microorganisms and the immature intestinal epithelium, and emerging evidence has clearly placed the spotlight on an important and exciting role for TLRs, particularly TLR4, in NEC pathogenesis. In premature infants, TLR4 signaling within the small intestinal epithelium regulates apoptosis, proliferation and migration of enterocytes, affects the differentiation of goblet cells, and reduces microcirculatory perfusion, which in combination result in the development of NEC. This review will explore the signaling properties of TLRs on hematopoietic and non-hematopoietic cells, and will examine the role of TLR4 signaling in the development of NEC. In addition, the effects of dampening TLR4 signaling using synthetic and endogenous TLR4 inhibitors and active components from amniotic fluid and human milk on NEC severity will be reviewed. In so doing, we hope to present a balanced approach to the understanding of the role of TLRs in both immunity and disease pathogenesis, and to dissect the precise roles for TLR4 in both the cause and therapeutic intervention of necrotizing enterocolitis.

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IL-1 receptor-associated kinase M downregulates DSS-induced colitis†

Abstract: This is the first report examining the role of IRAK-M in colitis. We find that IRAK-M is of critical importance in downregulating induction and progression of DSS colitis, and thereby suggesting that IRAK-M might be a target for future interventional therapies.

Cited by 27 publications

References 52 publications

Enhanced Mucosal Defense and Reduced Tumor Burden in Mice with the Compromised Negative Regulator IRAK-M

Enhanced Mucosal Defense and Reduced Tumor Burden in Mice with the Compromised Negative Regulator IRAK-M

Increased production of soluble TLR2 by lamina propria mononuclear cells from ulcerative colitis patients

Toll-like receptor regulation of intestinal development and inflammation in the pathogenesis of necrotizing enterocolitis

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