The Toll–Interleukin-1 Receptor Member SIGIRR Regulates Colonic Epithelial Homeostasis, Inflammation, and Tumorigenesis

Xiao, Hui; Gulen, Muhammet F.; Qin, Jinzhong; Yao, Jinrong; Bulek, Katarzyna; Kish, Danielle D.; Altuntas, Cengiz Z.; Wald, David N.; Ma, Cun‐Gen; Zhou, Hang; Tuohy, Vincent K.; Fairchild, Robert L.; Motte, Carol de la; Cua, Daniel; Vallance, Bruce A.; Li, Xiaoxia

doi:10.1016/j.immuni.2007.02.012

Cited by 284 publications

(297 citation statements)

References 31 publications

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“…This suggests that TLR/IL-1R-induced hyperactivation of NF-κB could be sufficient for promoting intestinal inflammation and thus points to an important role for bacteria in this process. Moreover, complementation of Sigirr -/-mice with a transgene expressing SIGIRR specifically in IECs rescued their DSS-sensitive phenotype, showing that an epithelial-specific function of SIGIRR protects mice from DSS-induced colitis [27]. In line with this observation, IEC-specific deletion of the essential NF-κB negative feedback regulator A20 was recently shown to sensitize mice to DSS-induced intestinal inflammation [30].…”

Section: Detrimental Role For Nf-κb Activation In the Intestinementioning

confidence: 75%

“…Mice lacking CYLD show increased sensitivity to dextran sodium sulfate (DSS)-induced colitis, presumably due to an exacerbated response of CYLDdeficient immune cells to the destruction of the epithelial barrier by the DSS treatment [24]. Similarly, mice lacking single immunoglobulin IL-1R-related (SIGIRR) develop more severe colon inflammation after DSS treatment [25][26][27]. Although both CYLD and SIGIRR are negative regulators of NF-κB activity, CYLD deubiquitinates essential NF-κB signaling proteins such as NEMO and thereby limits NF-κB activation upon various stimuli [28], whereas SIGIRR selectively inhibits NF-κB activation induced by members of the TLR/IL-1R family [29].…”

Section: Detrimental Role For Nf-κb Activation In the Intestinementioning

confidence: 99%

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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: Detrimental Role For Nf-κb Activation In the Intestinementioning

confidence: 75%

Section: Detrimental Role For Nf-κb Activation In the Intestinementioning

confidence: 99%

NF-κB in the regulation of epithelial homeostasis and inflammation

2010

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“…This has two important implications: First, epithelial cells at non-sterile surfaces have to regulate their TLR sensitivity to avoid continuous threat of inflammation and, second, organ-specific mechanisms of regulating immunity have to exist. The first fact has now been intensively studied and multiple mechanisms including threshold regulation of TLR stimulation [6,10], anatomical sequestration [14,26], inhibitory signaling molecules [27,28], coreceptor modulation [6] and specific signaling pathways [29] have been described. The second hypothesis was the subject of this study.…”

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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“…It inhibits signalling through TLRs and the IL-1 receptor and is highly expressed in the intestinal mucosa. Deficiency in the gene that encodes TIR8 is associated with increased susceptibility to intestinal inflammation and carcinogenesis 34,35 . Thus, the balance of inhibitors and activators tunes the extent to which the NF-κB pathway operates as an endogenous tumour promoter.…”

Section: Key Factors In Cancer-related Inflammationmentioning

confidence: 99%

Cancer-related inflammation

Mantovani

Allavena

Sica

et al. 2008

Nature

9,762

112

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Links between cancer and inflammation were first made in the nineteenth century, on the basis of observations that tumours often arose at sites of chronic inflammation and that inflammatory cells were present in biopsied samples from tumours 1 . The idea that these processes are connected was out of favour for more than a century, but there has been a recent resurgence in interest. Several lines of evidence 1-4 (Box 1) -based on a range of findings, from epidemiological studies of patients to molecular studies of genetically modified mice -have led to a general acceptance that inflammation and cancer are linked.Epidemiological studies have shown that chronic inflammation predisposes individuals to various types of cancer. It is estimated that underlying infections and inflammatory responses are linked to 15-20% of all deaths from cancer worldwide 1 . There are many triggers of chronic inflammation that increase the risk of developing cancer. Such triggers include microbial infections (for example, infection with Helicobacter pylori is associated with gastric cancer and gastric mucosal lymphoma), autoimmune diseases (for example, inflammatory bowel disease is associated with colon cancer) and inflammatory conditions of unknown origin (for example, prostatitis is associated with prostate cancer). Accordingly, treatment with non-steroidal anti-inflammatory agents decreases the incidence of, and the mortality that results from, several tumour types [5][6][7] .The hallmarks of cancer-related inflammation include the presence of inflammatory cells and inflammatory mediators (for example, chemokines, cytokines and prostaglandins) in tumour tissues, tissue remodelling and angiogenesis similar to that seen in chronic inflammatory responses, and tissue repair. These signs of 'smouldering' inflammation 2 are also present in tumours for which a firm causal relationship to inflammation has not been established (for example, breast tumours). Indeed, inflammatory cells and mediators are present in the microenvironment of most, if not all, tumours, irrespective of the trigger for development.Studies of genetically modified mice, adoptive-transfer experiments in mice, and analyses of human tumours have allowed researchers to begin to unravel the molecular pathways that link inflammation and cancer. Here we review current knowledge of the molecular and cellular pathways that link inflammation and cancer, and we describe how these pathways suppress effective antitumour immunity during tumour progression. We also discuss how cancer-related inflammation affects many aspects of malignancy, including the proliferation and survival of malignant cells, angiogenesis (which is required for the survival of cells within tumours of a certain size), tumour metastasis, and tumour response to chemotherapeutic drugs and hormones.Advances in understanding the genetic pathways involved in cancer have led to the development of a range of therapies that target malignant cells. Understanding the pathways involved in cancer-related inflammation could ...

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The Toll–Interleukin-1 Receptor Member SIGIRR Regulates Colonic Epithelial Homeostasis, Inflammation, and Tumorigenesis

Cited by 284 publications

References 31 publications

NF-κB in the regulation of epithelial homeostasis and inflammation

NF-κB in the regulation of epithelial homeostasis and inflammation

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

Cancer-related inflammation

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