Endogenous Interleukin-4 Promotes Tumor Development by Increasing Tumor Cell Resistance to Apoptosis

Li, Zhiguang; Jiang, Jing; Wang, Zibing; Zhang, Jinhua; Xiao, Mingjie; Wang, Chunhui; Yu, Lu; Qin, Zhihai

doi:10.1158/0008-5472.can-08-0449

Cited by 91 publications

(82 citation statements)

References 36 publications

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“…In the presence of IL-4, these cells expressed high levels of cellular Bcl-x L , cFLIP or both of them. The investigators in our group observed the similar effects of IL-4 on murine fibrosarcoma (56), and using IL-4R competent or deficient tumor cells of the same origin demonstrated that IL-4 promotes tumor growth in vivo (Figure 2). …”

Section: Tumor Cells Express Elevated Amount Of Il-4rmentioning

confidence: 58%

Paradoxical Roles of IL-4 in Tumor Immunity

2009

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Section: Tumor Cells Express Elevated Amount Of Il-4rmentioning

confidence: 58%

Paradoxical Roles of IL-4 in Tumor Immunity

2009

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“…A series of studies, including ours, demonstrate a critical requirement for IFN-␥ in tumor growth inhibition (10 -13). In addition, high levels of exogenous TNF-␣ or IL-4 also mediate the suppression of tumor growth through the IFN-␥ pathway (14,15), highlighting the key role of IFN-␥ in tumor immunity (10 -16). Consistent with the pleiotropic activities of this cytokine, the IFN-␥ receptor (IFN-␥R) is expressed on almost all cell types (17)(18)(19).…”

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confidence: 99%

Responsiveness of Stromal Fibroblasts to IFN-γ Blocks Tumor Growth via Angiostasis

Yang

Qin

et al. 2009

The Journal of Immunology

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The importance of stromal cells for tumor is akin to soil for seed. However, the interaction among these cells is far from understood. In this study, we show that stromal fibroblasts exist not only during tumor progression but also during regression stage, together with immune effector cells. Coinjection of stromal fibroblasts with tumor cells often promotes tumor growth. However, the presence of IFN-γ significantly impairs the ability of these cells to promote tumor growth due to a reduced angiogenesis. The mechanism relies mainly on the IFN-γ-mediated down-regulation of vascular endothelial growth factor production by fibroblasts. The results reveal a novel link between immune cells and nonbone marrow-derived stromal cells, and define stromal fibroblasts as the main targets of IFN-γ in tumor immunity.

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“…IL-4 itself may affect tumor growth, especially on those that have abundant IL-4 receptors. The levels of expression of the IL-4 receptor correlated with the tumorigenic potential in a murine model (27). Several tumors appeared to be resistant to apoptosis, which is induced by chemotherapeutic agents or CD95 ligation, in an IL-4-dependent manner.…”

Section: Discussionmentioning

confidence: 98%

“…IL-4 seemed to modify the immunological functions of effector cells. The cultivation of naïve CD8 + T cells in the presence of IL-4 resulted in poor cytolytic function in the cells by reducing the levels of perforin and granzymes (27,28). Whether an immune response is predominantly Th1 or Th2 may depend on a number of other factors, such as mouse strain, kind of tumor, amount of tumor antigen, and the amount of cytokine (29,30).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-4 and CpG oligonucleotide therapy suppresses the outgrowth of tumors by activating tumor-specific Th1-type immune responses

et al. 2012

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Abstract. Because IL-4 and CpG oligodeoxynucleotides (CpG-ODNs) are immune stimulants, we evaluated the antitumor effects of IL-4 gene therapy and CpG-ODN treatment in a poorly immunogenic murine cancer model. We used a murine colorectal cancer MC38 cell line overexpressing the IL-4 gene (MC38-IL4). Incubation with MC38-IL4 and CpG-ODN enhanced bone marrow-derived dendritic cell (DC) maturation in vitro. In addition, interferon (IFN)-γ production was significantly increased in naïve splenocytes after they were coincubated with MC38-IL4 and CpG-ODN. When mice bearing MC38 wild-type tumors were inoculated subcutaneously with MC38-IL4 cells and CpG-ODN, the outgrowth of established parental tumors was significantly suppressed compared to those in the MC38-IL4-treated group (IL-4 vs. IL-4 + CpG-ODN, P= 0.015). A marked infiltration of CD8 + cells in the established parental tumors of mice treated with MC38-IL4 and CpG-ODN was confirmed by immunohistochemical analyses (MC38-IL4, 2.8±1.9 cells/field vs. MC38-IL4 + CpG-ODN, 20.7±15.3 cells/field, P=0.027). Significant tumor-specific cytolysis was detected when splenocytes of MC38-IL4 + CpG-ODN-treated mice were stimulated by γ-irradiated MC38-IL4 cells and CpG-ODN twice weekly in vitro and used as effector cells in a chromium-release assay (32.2±3.5% for MC38 cells vs. 3.2±1.1% for YAC-1 cells; at an effector to target ratio of 40). These results suggest that IL-4 and CpG-ODN treatment promotes potent Th1-type antitumor immune responses. Therefore, the combination of IL-4 gene therapy and CpG-ODN treatment for cancer should be evaluated in clinical trials.

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Endogenous Interleukin-4 Promotes Tumor Development by Increasing Tumor Cell Resistance to Apoptosis

Cited by 91 publications

References 36 publications

Paradoxical Roles of IL-4 in Tumor Immunity

Paradoxical Roles of IL-4 in Tumor Immunity

Responsiveness of Stromal Fibroblasts to IFN-γ Blocks Tumor Growth via Angiostasis

Interleukin-4 and CpG oligonucleotide therapy suppresses the outgrowth of tumors by activating tumor-specific Th1-type immune responses

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