Figure 3.

Opposing effects of IL-4 on tumorigenesis through its impact on different cell types in the tumor microenvironment. IL-4 can exert tumorpromoting functions by enhancing the EGF/CSF-1 paracrine loop between TAMs and tumor cells, and through induction of cathepsin enzyme activity in TAMs. It also impedes T cell-mediated immunity against tumor cells through polarization of CD8⁺ T cells to type 2 cytotoxic T cells (Tc2), or via impairment of granzyme-mediated tumor-specific cytotoxicity of CD8⁺ T cells. IL-4 has also been shown to induce angiogenesis by stimulating the production of soluble VCAM-1 from endothelial cells. Additionally, IL-4 protects tumor cells from apoptosis through upregulation of anti-apoptotic proteins, and enhances cell proliferation through activation of MAPK signaling pathways. On the other hand, IL-4 also exhibits anti-tumor effects through different mechanisms including recruitment and activation of innate immune cells, such as neutrophils, eosinophils and dendritic cells. CD8⁺ T cells have been found to mediate the anti-tumor activities of IL-4. In some types of cancers, IL-4 can induce apoptosis of tumor cells. IL-4 has also been reported to inhibit angiogenesis directly through its effects on endothelial cells or indirectly through effects on tumor stromal fibroblasts.