TLRs in the Gut.IV. Negative regulation of Toll-like receptors and intestinal homeostasis: addition by subtraction

Shibolet, Oren; Podolsky, Daniel K.

doi:10.1152/ajpgi.00531.2006

Cited by 191 publications

(159 citation statements)

References 30 publications

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“…Under normal conditions, intestinal macrophages and dendritic cells are regulated to secrete low levels of proinflammatory cytokines, such as IL-12, in response to such bacteria. Various mechanisms, including constitutive expression of inhibitory transcription factors in the mucosal phagocytes and a supply of suppressive mediators by intestinal epithelial cells, have been proposed to explain the mechanism by which proinflammatory cytokine responses are controlled (48,49). In the current study, we clearly show that LTA and WTA can convert a predominant IL-12 response to specific bacteria into a predominant IL-10 response.…”

Section: Discussionsupporting

confidence: 52%

Bacterial Teichoic Acids Reverse Predominant IL-12 Production Induced by Certain Lactobacillus Strains into Predominant IL-10 Production via TLR2-Dependent ERK Activation in Macrophages

Kaji

Kiyoshima-Shibata

Nagaoka

et al. 2010

The Journal of Immunology

162

119

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Section: Discussionsupporting

confidence: 52%

Bacterial Teichoic Acids Reverse Predominant IL-12 Production Induced by Certain Lactobacillus Strains into Predominant IL-10 Production via TLR2-Dependent ERK Activation in Macrophages

Kaji

Kiyoshima-Shibata

Nagaoka

et al. 2010

The Journal of Immunology

162

119

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“…Negative regulatory molecules may play a role in regulating epithelial TLR signaling, including peroxisome proliferatoractivated receptor-γ; the cytoplasmic zinc finger protein, A20; and the negative regulator of TLR signaling, IRAK-M, as has been reviewed recently (199). The relevance of these molecules to signaling within epithelial cells remains to be definitely demonstrated.…”

Section: Peaceful Coexistence: Mechanisms Allowing Epithelial Cells Tmentioning

confidence: 99%

No Longer an Innocent Bystander: Epithelial Toll-Like Receptor Signaling in the Development of Mucosal Inflammation

Gribar

Richardson

Sodhi

et al. 2008

Mol Med

142

109

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Diseases of mucosal inflammation represent important causes of morbidity and mortality, and have led to intense research efforts to understand the factors that lead to their development. It is well accepted that a breakdown of the normally impermeant epithelial barrier of the intestine, the lung, and the kidney is associated with the development of inflammatory disease in these organs, yet significant controversy exists as to how this breakdown actually occurs, and how such a breakdown may lead to inflammation. In this regard, much work has focused upon the role of the epithelium as an "innocent bystander," a target of a leukocyte-mediated inflammatory cascade that leads to its destruction in the mucosal inflammatory process. However, recent evidence from a variety of laboratories indicates that the epithelium is not merely a passive component in the steps that lead to mucosal inflammation, but is a central participant in the process. In addressing this controversy, we and others have determined that epithelial cells express Toll-like receptors (TLRs) of the innate immune system, and that activation of TLRs by endogenous and exogenous ligands may play a central role in determining the balance between a state of "mucosal homeostasis," as is required for optimal organ function, and "mucosal injury," leading to mucosal inflammation and barrier breakdown. In particular, activation of TLRs within intestinal epithelial cells leads to the development of cellular injury and impairment in mucosal repair in the pathogenesis of intestinal inflammation, while activation of TLRs in the lung and kidney may participate in the development of pneumonitis and nephritis respectively. Recent work in support of these concepts is extensively reviewed, while essential areas of further study that are required to determine the significance of epithelial TLR signaling during states of health and disease are outlined.

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“…Evidence for TLR4/MD-2 delivering negative signals is not without precedent. It is a characteristic of high-dose LPS tolerance, in which sustained LPS signaling can lead to immune suppression (43)(44)(45)(46). Furthermore, antagonist derivatives of LPS were shown to dampen the proinflammatory cascade associated with sepsis (38).…”

mentioning

confidence: 99%

Soluble CD83 Inhibits T Cell Activation by Binding to the TLR4/MD-2 Complex on CD14+ Monocytes

Horvatinovich

Grogan

Norris

et al. 2017

The Journal of Immunology

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The transmembrane protein CD83, expressed on APCs, B cells, and T cells, can be expressed as a soluble form generated by alternative splice variants and/or by shedding. Soluble CD83 (sCD83) was shown to be involved in negatively regulating the immune response. sCD83 inhibits T cell proliferation in vitro, supports allograft survival in vivo, prevents corneal transplant rejection, and attenuates the progression and severity of autoimmune diseases and experimental colitis. Although sCD83 binds to human PBMCs, the specific molecules that bind sCD83 have not been identified. In this article, we identify myeloid differentiation factor-2 (MD-2), the coreceptor within the TLR4/MD-2 receptor complex, as the high-affinity sCD83 binding partner. TLR4/MD-2 mediates proinflammatory signal delivery following recognition of bacterial LPSs. However, altering TLR4 signaling can attenuate the proinflammatory cascade, leading to LPS tolerance. Our data show that binding of sCD83 to MD-2 alters this signaling cascade by rapidly degrading IL-1R–associated kinase-1, leading to induction of the anti-inflammatory mediators IDO, IL-10, and PGE2 in a COX-2–dependent manner. sCD83 inhibited T cell proliferation, blocked IL-2 secretion, and rendered T cells unresponsive to further downstream differentiation signals mediated by IL-2. Therefore, we propose the tolerogenic mechanism of action of sCD83 to be dependent on initial interaction with APCs, altering early cytokine signal pathways and leading to T cell unresponsiveness.

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TLRs in the Gut.IV. Negative regulation of Toll-like receptors and intestinal homeostasis: addition by subtraction

Cited by 191 publications

References 30 publications

Bacterial Teichoic Acids Reverse Predominant IL-12 Production Induced by Certain Lactobacillus Strains into Predominant IL-10 Production via TLR2-Dependent ERK Activation in Macrophages

Bacterial Teichoic Acids Reverse Predominant IL-12 Production Induced by Certain Lactobacillus Strains into Predominant IL-10 Production via TLR2-Dependent ERK Activation in Macrophages

No Longer an Innocent Bystander: Epithelial Toll-Like Receptor Signaling in the Development of Mucosal Inflammation

Soluble CD83 Inhibits T Cell Activation by Binding to the TLR4/MD-2 Complex on CD14+ Monocytes

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