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Melphalan-Induced Expression of IFN- in MOPC-315 Tumor-Bearing Mice and Its Importance for the Up-Regulation of TNF- Expression¹

Department of Biochemistry and Molecular Biology, University of Illinois, Chicago, IL 60612

We have previously shown that administration of a low-dose of melphalan (L-phenylalanine mustard; L-PAM) to mice bearing a large s.c. MOPC-315 tumor leads to up-regulation of TNF- expression, which is first evident at the mRNA level at 24 h after the chemotherapy. In this study, we show accumulation of IFN- mRNA in the spleen and tumor nodule of such mice as early as 1 h after the chemotherapy followed by elevated production of IFN- protein. IFN- protein in turn was found to be important for the L-PAM-induced up-regulation of TNF- expression, as neutralization of IFN- inhibited the L-PAM-induced up-regulation of TNF- mRNA expression in MOPC-315 tumor cells. In addition, L-PAM failed to up-regulate TNF- expression in spleen cells from mice in which signaling by IFN- is deficient. Studies into the mechanism through which L-PAM leads to rapid accumulation of IFN- mRNA revealed that it requires de novo RNA synthesis, indicating that the regulation is at the transcriptional level. However, it did not require de novo protein synthesis, indicating that activation of pre-existing transcription factors is sufficient for IFN- gene expression. The L-PAM-induced accumulation of IFN- mRNA was mimicked with H₂O₂ and was prevented with the antioxidant N-acetyl-L-cysteine, indicating that reactive oxygen species are involved in the transcriptional regulation of L-PAM-induced IFN- gene expression. Thus, the IFN- gene is an early response gene that is activated in response to L-PAM via a pathway that involves reactive oxygen species, and IFN- in turn plays an important role in L-PAM-induced TNF- up-regulation.

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