Endogenous interleukin-4 promotes tumor development by increasing tumor cell resistance to 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.
Li
Zhiguang
Z
National Laboratory of Biomacromolecules, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Graduate School of Chinese Academy of Sciences, Institute of Biophysics, Beijing, China.
Jiang
Jing
J
Wang
Zibing
Z
Zhang
Jinhua
J
Xiao
Mingjie
M
Wang
Chunhui
C
Lu
Yu
Y
Qin
Zhihai
Z
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D015153:Blotting, Western; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D017931:DNA Primers; D005434:Flow Cytometry; D007150:Immunohistochemistry; D015847:Interleukin-4 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000473:pathology*; D016133:Polymerase Chain Reaction; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000502:physiology
D017931:DNA Primers; D019948:Receptors, Interleukin-4; D015847:Interleukin-4