Role of Toll-like Receptors in Spontaneous Commensal-Dependent Colitis

Rakoff-Nahoum, Seth; Hao, Liming; Medzhitov, Ruslan

doi:10.1016/j.immuni.2006.06.010

Cited by 325 publications

(275 citation statements)

References 58 publications

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“…An interesting question would be whether, in a physiological setting, low-dose TLR stimulation contributes to such a homeostatic circuit. Indeed, it has recently been shown that epithelium integrity is dependent on intact MyD88 signaling in lung as well as intestinal non-infectious disease models [11,35,36].…”

Section: Discussionmentioning

confidence: 99%

Airway epithelial cells modify immune responses by inducing an anti‐inflammatory microenvironment

et al. 2008

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The upper airways are prone to contact with pathogenic as well as non-pathogenic microbes, therefore immune recognition principles have to be tightly controlled. Here we show that human BEAS-2B bronchial epithelial cells inhibited secretion of the proinflammatory cytokines TNF-a and IL-12 by monocytes, macrophages and dendritic cells. This inhibitory effect could be transferred by supernatant of resting BEAS-2B cells and was also observed when primary murine tracheal epithelial cells were prepared. In contrast to inhibition of pro-inflammatory cytokine secretion epithelial cell-conditioned dendritic cells showed increased expression of IL-10 and arginase-1, thus displaying properties of alternative activation. Accordingly, Toll-like receptor-mediated up-regulation of CD40, CD86 and PD-L2 (CD273) on murine dendritic cells was reduced in the presence of bronchial epithelial cell supernatant. However, expression of negative regulatory PD-L1 (CD274) was increased and dendritic cell induced proliferation of T lymphocytes was diminished. Epithelial cells also showed a direct inhibitory effect on T lymphocyte proliferation and this was due to the constitutive secretion of TGF-b by bronchial epithelial cells. Moreover, epithelial cell-conditioned T lymphocytes showed increased differentiation towards IL-10-producing Tr1 cells. The results indicate that bronchial epithelial cells induce a noninflammatory microenvironment that regulates local immune homeostasis.

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Section: Discussionmentioning

confidence: 99%

Airway epithelial cells modify immune responses by inducing an anti‐inflammatory microenvironment

et al. 2008

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“…Moreover, in IL-10-deficient mice, the development of spontaneous colitis requires commensal flora and an intact TLR-MyD88 signaling pathway. 76 More direct evidence for the antigenic role of commensal flora comes from studies of immune responses towards specific gut bacterial antigens. For example, spontaneously colitic C3H/HeJBir mice (CBir), generated by selective breeding of C3H/HeJ mice for the colitic phenotype, show increased B-cell and T-cell reactivity towards bacterial antigens, 77 and transfer of CD4 + T cells from colitic CBir mice causes colitis in immunodeficient recipient mice.…”

Section: Role For Bacterial Antigens In Ibdmentioning

confidence: 99%

The role of T‐regulatory cells and Toll‐like receptors in the pathogenesis of human inflammatory bowel disease

Himmel¹,

Hardenberg²,

Piccirillo³

et al. 2008

Immunology

131

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SummaryTwo related chronic inflammatory diseases, Crohn's disease and ulcerative colitis, are together often referred to as inflammatory bowel disease (IBD). Current treatment options are not curative, and patients face lifelong therapy and debilitation. IBD is thought to be the product of a combination of genetic and environmental factors that result in the abnormal regulation of immune responses. Experimental models have demonstrated that normal CD4 + T-regulatory (Treg) cell responses and commensal bacteria are required for the maintenance of gut immune homeostasis. Recent evidence that CD4 + T cells express Toll-like receptors (TLRs) and respond directly to TLR ligands, suggests that signals from commensal bacteria may directly affect T-cell responses in the gut. In this review, we focus on evidence that defects in Treg cells may underlie IBD in humans. In addition, we discuss evidence that direct signaling via TLRs to T cells can affect IBD and that T-cell-dependent responses to bacterial proteins, such as flagellin, are central to the aetiology of this disease.

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“…Recent studies highlighted the importance of both adaptive and innate immunity in IBD pathogenesis (3)(4)(5).…”

mentioning

confidence: 99%

The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis

Sheibanie

Yen

Khayrullina

et al. 2007

The Journal of Immunology

252

196

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Although Crohn’s disease has been traditionally considered to be Th1-mediated, the newly identified Th17 cells emerged recently as crucial participants. Th1/Th17 differentiation is controlled primarily by the IL-12 family of cytokines secreted by activated dendritic cells (DCs) and macrophages. IL-23 and IL-12/IL-27 have opposite effects, supporting the Th17 and Th1 phenotypes, respectively. We found that PGE2, a major lipid mediator released in inflammatory conditions, shifts the IL-12/IL-23 balance in DCs in favor of IL-23, and propose that high levels of PGE2 exacerbate the inflammatory process in inflammatory bowel disease through the IL-23→IL-17 axis. We assessed the effects of PGE2 on IL-12, IL-27, and IL-23 and found that PGE2 promotes IL-23, inhibits IL-12 and IL-27 expression and release from stimulated DCs, and subsequently induces IL-17 production in activated T cells. The effects of PGE2 are mediated through the EP2/EP4 receptors on DCs. In vivo, we assessed the effects of PGE analogs in an experimental model for inflammatory bowel disease and found that the exacerbation of clinical symptoms and histopathology correlated with an increase in IL-23 and IL-17, a decrease in IL-12p35 expression in colon and mesenteric lymph nodes, and a substantial increase in the number of infiltrating neutrophils and of CD4+IL-17+ T cells in the colonic tissue. These studies suggest that high levels of PGE2 exacerbate the inflammatory process through the preferential expression and release of DC-derived IL-23 and the subsequent support of the autoreactive/inflammatory Th17 phenotype.

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Role of Toll-like Receptors in Spontaneous Commensal-Dependent Colitis

Cited by 325 publications

References 58 publications

Airway epithelial cells modify immune responses by inducing an anti‐inflammatory microenvironment

Airway epithelial cells modify immune responses by inducing an anti‐inflammatory microenvironment

The role of T‐regulatory cells and Toll‐like receptors in the pathogenesis of human inflammatory bowel disease

The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis

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