Immunomodulatory effect of decoy receptor 3 on the differentiation and function of bone marrow-derived dendritic cells in nonobese diabetic mice: from regulatory mechanism to clinical implication

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The soluble decoy receptor 3 (DcR3) is a member of the TNFR superfamily. Because DcR3 is up-regulated in tumor tissues and is detectable in the sera of cancer patients, it is regarded as an immunosuppressor to down-regulate immune responses. To understand the function of DcR3 in vivo, we generated transgenic mice overexpressing DcR3 systemically. In comparison with HNT-TCR (HNT) transgenic mice, up-regulation of IL-4 and IL-10 and down-regulation of IFN-γ, IL-12, and TNF-α were observed in the influenza hemagglutinin126–138 peptide-stimulated splenocytes of HNT-DcR3 double-transgenic mice. When infected with Listeria monocytogenes, DcR3 transgenic mice show attenuated expression of IFN-γ as well as increased susceptibility to infection. The Th2 cell-biased phenotype in DcR3 transgenic mice is attributed to decreased IL-2 secretion by T cells, resulting in the suppression of IL-2 dependent CD4+ T cell proliferation. This suggests that DcR3 might help tumor growth by attenuating the Th1 response and suppressing cell-mediated immunity.

Section: Ecoy Receptor 3 (Dcr3)mentioning

confidence: 54%

Section: Ecoy Receptor 3 (Dcr3)mentioning

confidence: 99%

Attenuation of Th1 Response in Decoy Receptor 3 Transgenic Mice

Hsu

Chang

et al. 2005

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“…Our recent studies suggested that DcR3, like other members of the TNFR superfamily, is capable of triggering "reverse signaling" to modulate monocyte differentiation and function (26 -30). DcR3 was demonstrated to interfere with the differentiation and maturation of dendritic cells from monocytes, which leads to a skewing of the T cell response toward the Th2 phenotype (26,29). This Th1-suppressing effect of DcR3 also supports its critical role in cancer development.…”

mentioning

confidence: 76%

“…To date, the identity of the novel ligand(s) for DcR3 remains unclear and needs further investigation. However, reverse signaling has been shown to mediate several biological effects of DcR3 in monocytes, macrophages, and dendritic cells (26,28,30,60,62).…”

Section: Discussionmentioning

confidence: 99%

Decoy Receptor 3 Increases Monocyte Adhesion to Endothelial Cells via NF-κB-Dependent Up-Regulation of Intercellular Adhesion Molecule-1, VCAM-1, and IL-8 Expression

Yang

Hsieh

et al. 2005

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Decoy receptor 3 (DcR3), a soluble receptor for FasL, LIGHT and TL1A, is highly expressed in cancer cells. We show that pretreatment of HUVECs with DcR3 enhances the adhesion of THP-1 and U937 cells and primary monocytes. A similar stimulatory effect of DcR3 on THP-1 adhesion was also observed in human microvascular endothelial cells (HMVECs). Flow cytometry and ELISA showed that DcR3-treated HUVECs exhibited significant increases in ICAM-1 and VCAM-1 expression. We also demonstrate the ability of DcR3 to stimulate the secretion of IL-8 by HUVECs. RT-PCR and reporter assays revealed that the expression of adhesion molecules and IL-8 are regulated at the level of gene transcription. Experiments with pyrrolidine dithiocarbamate indicated the involvement of an NF-κB signaling pathway. DcR3 was found to induce IκB kinase activation, IκB degradation, p65 nuclear translocation, and NF-κB DNA-binding activity. The enhancement by DcR3 of cell adhesion to HUVECs was not mimicked by the TL1A-Ab, which has been shown in our previous work to be a neutralizing Ab against TL1A, thereby inducing HUVECs angiogenesis. Moreover, DcR3-induced cell adhesion could be detected in human aortic endothelial cells (ECs) in which TL1A expression is lacking. Together, our data demonstrate that DcR3 increases monocyte adhesion to ECs via NF-κB activation, leading to the transcriptional up-regulation of adhesion molecules and IL-8 in ECs. This novel action appears not to be due to TL1A neutralization, but occurs through an as yet undefined target(s). This study implicates DcR3 in the relationship between inflammation and cancer development.

“…We (37,46,47) and Han et al (43) demonstrated that DcR3 acts as a neutralizing "decoy receptor," as well as an "effector" to skew host immunity toward Th2-dominant responses by influencing the activation and differentiation of dendritic cells. In this study, we demonstrated an additional immunomodulatory mechanism of DcR3 contributing to tumor progression in vivo via the induction of TAMs.…”

Section: Discussionmentioning

confidence: 99%

Decoy Receptor 3 Enhances Tumor Progression via Induction of Tumor-Associated Macrophages

Tai

Chang²,

Lan

et al. 2012

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Tumor-associated macrophages (TAMs) are the major component of tumor-infiltrating leukocytes. TAMs are heterogeneous, with distinct phenotypes influenced by the microenvironment surrounding tumor tissues. Decoy receptor 3 (DcR3), a member of the TNFR superfamily, is overexpressed in tumor cells and is capable of modulating host immunity as either a neutralizing decoy receptor or an effector molecule. Upregulation of DcR3 has been observed to correlate with a poor prognosis in various cancers. However, the mechanisms underlying the DcR3-mediated tumor-promoting effect remain unclear. We previously demonstrated that DcR3 modulates macrophage activation toward an M2-like phenotype in vitro and that DcR3 downregulates MHC class II expression in TAMs via epigenetic control. To investigate whether DcR3 promotes tumor growth, CT26-DcR3 stable transfectants were established. Compared with the vector control clone, DcR3-transfectants grew faster and resulted in TAM infiltration. We further generated CD68 promoter-driven DcR3 transgenic (Tg) mice to investigate tumor growth in vivo. Compared with wild-type mice, macrophages isolated from DcR3-Tg mice displayed higher levels of IL-10, IL-1ra, Ym1, and arginase activity, whereas the expression of IL-12, TNF-α, IL-6, NO, and MHC class II was downregulated. Significantly enhanced tumor growth and spreading were observed in DcR3-Tg mice, and the enhanced tumor growth was abolished by arginase inhibitor N-ω-hydroxy-l-norarginine and histone deacetylase inhibitor sodium valproate. These results indicated that induction of TAMs is an important mechanism for DcR3-mediated tumor progression. Our findings also suggest that targeting DcR3 might help in the development of novel treatment strategies for tumors with high DcR3 expression.