MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18

Abstract

Signaling through the adaptor protein myeloid differentiation factor 88 (MyD88) promotes carcinogenesis in several cancer models. In contrast, MyD88 signaling has a protective role in the development of azoxymethane (AOM)/dextran sodium sulfate (DSS) colitis-associated cancer (CAC). The inability of Myd88−/− mice to heal ulcers generated upon injury creates an altered inflammatory environment that induces early alterations in expression of genes encoding proinflammatory factors, as well as pathways regulating cell proliferation, apoptosis, and DNA repair, resulting in a dramatic increase in adenoma formation and progression to infiltrating adenocarcinomas with frequent clonal mutations in the β-catenin gene. Others have reported that toll-like receptor (Tlr) 4–deficient mice have a similar susceptibility to colitis to Myd88-deficient mice but, unlike the latter, are resistant to CAC. We have observed that mice deficient for Tlr2 or Il1r do not show a differential susceptibility to colitis or CAC. However, upon AOM/DSS treatment Il18−/− and Il18r1−/− mice were more susceptible to colitis and polyp formation than wild-type mice, suggesting that the phenotype of Myd88−/− mice is, in part, a result of their inability to signal through the IL-18 receptor. This study revealed a previously unknown level of complexity surrounding MyD88 activities downstream of different receptors that impact tissue homeostasis and carcinogenesis.

Aldara activates TLR7-independent immune defence

“…This finding indicates that Aldara also has an impact on the murine inflammasome in vivo. Furthermore, it implicates an attenuating effect of IL-18 on the inflammatory response to Aldara in vivo and fits the recent observations that IL-18 protects against colitis and colitis-associated cancer in mice 40 .…”

NF-κB in the regulation of epithelial homeostasis and inflammation

“…One important aspect of MyD88 signaling that needs to be taken into account is that this adaptor is not only involved in TLR signaling but also in signaling induced by members of the IL-1 family of cytokines. These cytokines have been implicated in the regulation of intestinal inflammation, since mice that lack essential inflammasome components and therefore cannot produce biologically active IL-1β and IL-18 are hypersensitive to DSS-induced colitis [60][61][62][63] Although impaired responses to either IL-1β or IL-18 were shown to enhance susceptibility to DSS-induced colitis [64][65][66], IL-18 was identified as the crucial inflammasome-derived cytokine that protects mice from intestinal inflammation [61,63]. Even though the cellular target of IL-18 is not clear, these observations raise the possibility that the increased susceptibility of Myd88 -/-or IEC-specific NF-κB-deficient mice to DSS-induced colitis might, at least in part, be caused by impaired IL-18 signaling.…”

ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

“…Such a model has enabled the determination that ISCs are the cells of origin in CRC (Barker et al, 2009;Zhu et al, 2009;Schepers et al, 2012). The expansion of ISCs in Xbp1 /(IEC) mice, and the desire to delineate the specific tumor-promoting role of Xbp1 deficiency specifically in IECs, prompted us to Epithelial Xbp1 suppresses tumor formation in Apc min/+ mice Inflammatory signaling is an important contributor to CAC but also to sporadic and familial CRC (Rakoff-Nahoum and Medzhitov, 2007; Lee et al, 2010), with overlapping and distinct inflammatory pathways being involved (Salcedo et al, 2010). ER stress in various organs, including the liver, skeletal muscle, adipose tissue (Ozcan et al, 2004;Gregor et al, 2009;Kars et al, 2010), and intestinal crypts (Hodin et al, 2011), is associated with obesity, which is epidemiologically closely associated with increased cancer incidence, most notably CRC (Calle et al, 2003).…”