IL-1-7 Differential roles of IL-1 alpha and IL-1 beta in the malignant process

Both IL-1β and IL-1α are produced by normal as well as malignant cells in the microenvironment of tumors. However, IL-1 β and IL-1 α differ dramatically in their effect on the malignant process. IL-1 α is active as a cell-associated cytokine in that the cytokine binds to DNA and acts a co-transcription factor. IL-1 α also is expressed as a transmembrane cytokine and activates adjacent cells via a juxtacrine mechanism. In contrast, IL-1 β is active only in its mature secreted form following cleavage by caspase-1. By using IL-1 knockout (KO) mice, which lack functional IL-1 α, IL-1 β, IL-1 α /IL-1 β (double KO) or the IL-1 receptor antagonist (IL-1Ra) mice, we have studied the role of IL-1 during the process of chemical carcinogenesis induced by 3-methylcholanthrene (3-MCA). Mice deficient in the naturally occurring IL-1Ra develop greater numbers of tumors, multiple metastases and prominent angiogenesis, each suggesting a role for IL-1 β promoting the malignant process; mice deficient in IL-1 β exhibited markedly reduced tumors. Host-derived IL-1 α was essential for the process of immunoediting the repertoire of the newly formed neoplastic cells. In IL-1 α KO mice, 3-MCA-induced tumors were highly immunogenic compared to WT mice. Also, expression of membrane-associated IL-1 α on malignant cells serves as an adjuvant increases the immunogenicity of tumor cells and leads to their eradication by activation of anti-tumor immunity. In promoting the malignant process, IL-1 β of host macrophage origin is highly inflammatory by increasing cell adhesion, tumor invasiveness and chemokines. IL-1 β also induces immune anergy, mediated by myeloid-derived suppressor cells, and contributes to the general immune suppression of cancer. In the process of tumor-mediated angiogenesis, IL-1 β of host origin was shown to mediate infiltration of myeloid cells of bone marrow origin into tumors, recruit endothelial precursors and activate local endothelial cells for VEGF production. Treatment of tumor-bearing mice with the IL-1Ra reduced tumor angiogenesis and invasiveness, supporting the therapeutic use of IL-1 β.