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

The increase of interleukin-4 (IL-A) level in tumor environment and the up-regulation of IL-4 receptor (IL-4R) on tumor cells have been long observed. However, their significance for tumor development has not been investigated. Here, we found that endogenous IL-4 promotes tumor growth because neutralizing IL-4 by IIBII monoclonal antibody (mAb) significantly delayed the growth of MCA205 fibrosarcoma. We also observed that tumor cells with higher IL-4R expression have more chances to survive in immunocompetent mice. To investigate how endogenons IL-4 influences tumor growth, we established a pair of tumor cells with or without IL-4R expression from the common parental cells. IL4R-competent tumors exhibit increased growth compared with its IL-4R-deficient counterparts when inoculated into syngeneic mice. This growth advantage was still kept in IL-4R knockout mice but was abrogated in mice given i.p. with IL-4 neutralizing mAb. In vitro analyses indicate that IL-4 neither affects the proliferation of tumor cells nor changes the expression of several immune-related molecules, such as MFIC-1, Fas, and B7-H3. Nonetheless, IL-4 up-regulates antiapoptotic gene expression in tumor cells and reduces apoptosis of tumor cells in vivo, as evidenced by real-time PCR, inummoblotting, and TUNEL staining. These findings were lielpfttl to understand the long clinical observation and revealed that endogenous IL-4, the product of host immune response, can be used by tumor cells to facilitate their growth. [Cancer Res 2008;68(21):8687-94]