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

¹ National Laboratory of Biomacromolecules, ² Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, and ³ Graduate School of Chinese Academy of Sciences, Institute of Biophysics, Beijing, China

Requests for reprints: Zhihai Qin, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China. Phone: 86-10-64888435; Fax: 86-10-64848257; E-mail: zhihai{at}ibp.ac.cn.

Key Words: endogenous interleukin-4 • interleukin-4 receptor • tumor cells • tumor growth • apoptosis

The increase of interleukin-4 (IL-4) 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 11B11 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 endogenous IL-4 influences tumor growth, we established a pair of tumor cells with or without IL-4R expression from the common parental cells. IL-4R–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 MHC-I, 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, immunoblotting, and TUNEL staining. These findings were helpful 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]

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