Abstract
TNFRSF21 (death receptor-6, DR6) is an orphan TNF receptor superfamily member and belongs to a subgroup of receptors called death receptors. DR6 is expressed ubiquitously with high expression in lymphoid organs, heart, brain and pancreas. Ectopic expression of DR6 in some cell lines leads to apoptosis and activation of the JNK and NF-κB pathways. Some tumor cells overexpress DR6, typically in conjunction with elevated anti-apoptosis molecules. DR6 deficient mice (DR6−/−) show normal development with no gross pathology in any major organs. In the absence of DR6, ligation of the TCR results in enhanced T-cell proliferation, activation and skewed Th2 cytokine production. Similarly, B-cells lacking Dr6 show increased proliferation, cell division and cell survival upon mitogenic stimulation (anti-CD40 and LPS) or BCR ligation. As a result, DR6−/− mice show increased Th2 immune responses to both T-dependent and -independent antigens. All those data indicate that DR6 plays an important regulatory role for the generation of adaptive immunity. More importantly, DR6−/− mice are resistant to EAE and allergic airway hypersensitivity, possibly as a result of a deficiency in the migration of antigen specific T-cells. Therefore, DR6 is a potential therapeutic target for treating inflammatory and autoimmune disease by means of biological intervention. In addition, DR6 is highly expressed in many tumor cell lines and tumor samples. Interestingly, both of its transcriptional and cell surface expression are regulated by the NF-κB pathway and metalloproteinase in some tumor cell lines, respectively. The role of DR6 as an apoptosis-inducing receptor is less clear and perhaps cell type dependent. Therefore, in addition to its roles in regulating immune responses, DR6 may also be involved in tumor cell survival and immune evasion, which is subject to future investigations.
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References
Hsu HC, Wu Y, Mountz JD. Tumor necrosis factor ligand-receptor superfamily and arthritis. Curr Dir Autoimmun 2006; 9:37–54.
Nash PT, Florin TH. Tumour necrosis factor inhibitors. Med J Aust 2005; 183:205–8.
Tanaka S, Nakamura K, Takahasi N et al. Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system. Immunol Rev 2005; 208:30–49.
van Horssen R, ten Hagen TL, Eggermont AM. TNF-alpha in cancer treatment: molecular insights, antitumor effects and clinical utility. Oncologist 2006; 11:397–408.
Lejeune FJ, Lienard D, Matter M et al. Efficiency of recombinant human TNF in human cancer therapy: Cancer Immun 2002; 6:6–22.
Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 2001; 104:487–501.
Pan G, Bauer JH, Haridas V et al. Identification and functional characterization of DR6, a novel death domain-containing TNF receptor. FEBS Lett 1998; 431:351–6.
Kasof GM, Lu JJ, Liu D et al. Tumor necrosis factor-alpha induces the expression of DR6, a member of the TNF receptor family, through activation of NF-kappaB. Oncogene 2001; 20:7965–75.
Liu J, Na S, Glasebrook A et al. Enhanced CD4+ T-cell proliferation and Th2 cytokine production in DR6-deficient mice. Immunity 2001; 15:23–34.
Schmidt CS, Liu J, Zhang T et al. Enhanced B-cell expansion, survival and humoral responses by targeting death receptor 6. Exp Med 2003; 197:51–62.
Zhao H, Yan M, Wang H et al. Impaired c-Jun amino terminal kinase activity and T-cell differentiation in death receptor 6-deficient mice. J Exp Med 2001; 194:1441–8.
Chow CW, Dong C, Flavell RA et al. c-Jun NH(2)-terminal kinase inhibits targeting of the protein phosphotase calcineurin to NFATcl. Mol Cell Biol 2000; 20:5227–34.
Liu J, Heuer JG, Na S et al. Accelerated onset and increased severity of acute graft-versus-host disease following adoptive transfer of DR6-deficient T-cells. J Immunol 2002; 169:3993–8.
Schmidt CS, Zhao J, Chain J et al. Resistance to myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis by death receptor 6-deficient mice. J Immunol 2005; 175:2286–92.
Kikly K, Liu L, Na S et al. The IL-23/TH(17) axis: therapeutic targets for autoimmune inflammation. Curr Opin Immunol 2006; 18:670–5. Review.
Touil T, Fitzgerald D, Zhang GX et al. Pathophysiology of interleukin-23 in experimental autoimmune encephalomyelitis. Drug News Perspect 2006; 19:77–83. Review.
Langrish CL, McKenzie BS, Wilson NJ et al. IL-12 and IL-23: master regulators of innate and adaptive immunity. Immunol Rev 2004; 202:96–105. Review.
Zhang-Hoover J, Finn P, Stein-Streilein J. Modulation of ovalbumin-induced airway inflammation and hyperreactivity by tolerogenic APC. J Immunol 2005; 175:7117–24.
Venkataraman C, Justen K, Zhao J et al. Death receptor-6 regulates the development of pulmonary eosinophilia and airway inflammation in a mouse model of asthma. Immunol Lett 2006; 106:42–7.
Tam EM, Morrison CJ, Wu YI et al. Membrane protease proteomics: isotope-coded affinity tag MS identification of undescribed MT1-matrix metalloproteinase substrates. PNAS 2004; 101:6917–22.
Enright AJ, Van Dongen S, Ouzounis CA. An efficient algorithm for large-scale detection of protein families. Nucl Acids Res 2002; 30:1575–84.
Krogh A, Larsson B, von Heijne G et al. Predicting transmembrane protein topology with a hidden Markov model: Application to complete genomes. J Mol Biol 2001; 305:567–80.
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Benschop, R., Wei, T., Na, S. (2009). Tumor Necrosis Factor Receptor Superfamily Member 21: TNFR-Related Death Receptor-6, DR6. In: Grewal, I.S. (eds) Therapeutic Targets of the TNF Superfamily. Advances in Experimental Medicine and Biology, vol 647. Springer, New York, NY. https://doi.org/10.1007/978-0-387-89520-8_13
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DOI: https://doi.org/10.1007/978-0-387-89520-8_13
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