Immunology. 2014 Feb;141(2):211-21.

TRAIL receptor deficiency sensitizes mice to dextran sodium sulphate-induced colitis and colitis-associated carcinogenesis.

Zhu J, Chen L, Shi J, Liu S, Liu Y, Zheng D.

National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

 

Abstract

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptor (TRAIL-R) play important roles in immune regulation and cancer cell death. Although TRAIL has been shown to induce chemokine release in various tumour cells, the function of TRAIL-R in the development of colitis and colitis-associated carcinogenesis has not been explored. In this study, we found that TRAIL-R-deficient mice exhibited a higher incidence of colitis and colitis-associated cancer than that of wild-type (WT) mice, and TRAIL-R expression was down-regulated in WT mice that were fed dextran sulphate sodium. Chemokines, including CCL2 and CXCL1, were highly expressed in the serum and inflammatory colon tissues of TRAIL-R(-/-) mice compared with WT mice, and TRAIL-R(-/-) mice showed a marked infiltration of immune cells during colitis. Hyperactivation of Janus kinase and nuclear factor-κB in colon epithelial cells was also observed, which correlated with the severity of colonic inflammation in TRAIL-R(-/-) mice. These data suggest that TRAIL-R plays a protective role in chemical-induced colon injury and negatively regulates mucosal immune responses. © 2013 John Wiley & Sons Ltd.

KEYWORDS: colitis, colitis-associated cancer, inflammation, tumour necrosis factor-related apoptosis-inducing ligand receptor

PMID: 24117005

 

SUPPLEMENT

TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a type-II membrane protein belonging to the TNF family. TRAIL preferentially induces apoptosis by binding its receptor 1 or 2 (TRAIL-R1 or TRAIL-R2, also termed as death receptor 4 or 5, DR4 or DR5) in transformed cells and tumor cells, but not in most normal cells. TRAIL and the agonistic antibodies against DR4 or DR5 are currently testing in clinical trials, indicating that they are promising therapeutics for cancers.

However, TRAIL/TRAIL-R signaling pathway also influences the regulation and homeostasis of the immune system. Upon stimulation, TRAIL can be highly expressed in a variety of cells in the innate and adaptive immune system. As we previously reported that TRAIL induced the expression of inflammatory chemokines, such as CCL4, CCL20, and CXCL2 in both TRAIL-resistant and TRAIL-sensitive tumor cells in an NF-kB-dependent manner [1]. These cytokines serve to recruit leucocytes in the response to the inflammatory conditions. We also showed that TRAIL induced chemotactic migration in THP-1 human leukemia cells, LPS-primed primary human monocytes, and LPS-stimulated BALB/c mouse monocytes [2], suggesting that TRAIL induces both apoptotic and prosurvival signaling pathways and plays broader roles in regulating immune processes.

In the present study, we also observed in the dextran sulfate sodium (DSS)-treated TRAIL-R-/- mouse models that CXCL1 and CCL2 were highly expressed in the serum and the inflammatory colon tissues. There were a marked infiltration of immune cells, such as T cells, and macrophages. Colonic epithelial cells of TRAIL-R-/- mice showed hyperactivation of JNK and NF-kB. (Figure S1) Furthermore, DSS-induced chronic colitis strongly contributed to the colorectal tumorigenesis. TRAIL-R deficiency facilitated the incidence and growth of colitis-associated colonic adenomas. (Figure S2) These results reveal a novel pathophysiologic role of TRAIL-R in Inflammatory bowel disease and colorectal cancer, whereby TRAIL-R may negatively regulate the mucosal immune response and tissue homeostasis in response to external stress or injury.

figure S1Figure S1 Summary of the finding on the role of TRAIL-R in DSS-induced colitis.

 

figure S2Figure S2 Schematic overview of the colon carcinogenesis model. All of the TRAIL-R-/- mice developed colon tumors, whereas only half of the WT mice developed tumors. TRAIL-R-/- mice had more average tumor number per mouse than WT mice. Arrows indicate colonic tumors. Bar, 1 cm.

 

References

  1. Tang W, Wang W, Zhang Y, Liu S, Liu Y, Zheng D. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced chemokine release in both TRAIL-resistant and TRAIL-sensitive cells via nuclear factor kappa B. FEBS J 2009; 276(2): 581-59
  2. Wei W, Wang D, Shi J, Xiang Y, Zhang Y, Liu S, Liu Y, Zheng D. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces chemotactic migration of monocytes via a death receptor 4-mediated RhoGTPase pathway. Mol Immunol 2010; 47(15): 2475-2484.

 

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