Innate immune signaling by Toll-like receptor-4 (TLR4) shapes the inflammatory microenvironment in colitis-associated tumors

Abstract

Patients with ulcerative colitis are at increased risk for developing colorectal cancer. We have shown that TLR4 is over-expressed in human colitis-associated cancer (CAC) and that mice deficient in TLR4 are markedly protected against colitis-associated neoplasia. We wished to elucidate the specific contributions of TLR4 signaling by myeloid cells and colonic epithelial cells (CEC) in colitis-associated tumorigenesis. TLR4-deficient mice or wild-type littermates (WT) were transplanted with bone marrow (BM) cells: TLR4-/-BM→WT mice (TLR4-expressing CEC) and WT BM→TLR4-/-mice (TLR4-expressing myeloid cells). Colitis-associated neoplasia was induced by azoxymethane (AOM 7.3mg/kg) injection and two cycles of dextran sodium sulfate (DSS) treatment. The number and size of dysplastic lesions were greater in TLR4-/-BM→WT mice than in WT BM→TLR4-/-mice (P<0.005). Histologically, TLR4-/-BM→WT mice had greater numbers of mucosal neutrophils and macrophages compared to WT BM→TLR4-/-mice. The chemokines KC and CCL2, important in recruitment of neutrophils and macrophages, respectively, were induced in mice expressing TLR4 in CEC rather than the myeloid compartment. The lamina propria infiltrate of mice expressing TLR4 in CEC was characterized by macrophages expressing Cox-2. Moreover, mice expressing TLR4 in CEC rather than the myeloid compartment had increased production of amphiregulin and EGFR activation. These findings indicate that TLR4 signaling on CEC is necessary for recruitment and activation of Cox-2 expressing macrophages and increasing the number and size of dysplastic lesions. Our results implicate innate immune signaling on CEC as a key regulator of a tumor-promoting microenvironment.

p120-catenin is essential for maintenance of barrier function and intestinal homeostasis in mice

“…The increased cell proliferation observed in both the small intestine ( Figure 6A) and colon (data not shown) may also be linked to inflammation (e.g., cytokine stimulation), as has been reported by others (60,61), or alternatively, to compensatory mechanisms that respond to excessive cell damage and exfoliation (30,47). Increased cell migration may be inflammation induced as well (62).…”

Protective function of interleukin 27 in colitis-associated cancer via suppression of inflammatory cytokines in intestinal epithelial cells

“…4D). Cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) are previously reported to be upregulated in CAC and accelerate the tumor formation, 16,34-36 but we did not observe the statistically significant difference of them in WSX-1 KO and WT IECs with CAC model (Fig. 4D).…”

“…But excessive TLR activation is often consequent in pathogenesis, previous study indicated that rather than immune cells, the function of TLR signaling pathway in IECs is much more significant in CAC. 16 Here, we report its anti-inflammatory function which exerts on TLR ligand-induced inflammation in intestinal epithelia cells. In our study, increased tumor incidence and tumor load were observed in WSX-1 deficient mice, along with enhanced tumor cell proliferation and MDSC accumulation.…”

“…Previous study has demonstrated that TLRs on IECs serve as more important pro-inflammatory factors in AOM/DSS-induced CAC model. 16 So, we examined whether loss of IL-27/WSX-1 signaling changes the production of inflammatory cytokines in IECs. We confirmed that subunits of IL-27 receptors, WSX-1 and gp130 were both detectable on EpCAM C IECs by Flow Cytometry (Fig.…”

“…15 By generating the bone marrow chimera, the same research group demonstrated that rather than haematopoietic cells, increased TLR4 signaling in IECs is more responsible for higher risk of inflammation-associated neoplasia. 16 Interleukin 27 (IL-27) is a heterodimeric cytokine combined with p28 and Epstein-Barr virus-induced gene (EBI3). 17 And its receptor is composed of WSX-1 (IL-27Ra) and gp130.…”