Anti-cancer agent OK432 induces manganese superoxide dismutase in human granulocytes.

Manganese superoxide dismutase (MnSOD) is a mitochondrial enzyme involved in scavenging O2-. OK432, a Streptococcal preparation, has anti-tumor activity and is also known to be a biological-response modifier. In this study, we have examined the regulation of MnSOD gene by OK432 in human granulocytes. Granulocytes had a low activity of MnSOD; OK432 increased MnSOD mRNA levels in a dose-dependent manner and its activity in granulocytes. OK432 also induced the MnSOD mRNA in HL60 promyelocytes, while not affecting the levels of MnSOD mRNA in human fibroblasts. Pre-treatment with either actinomycin D or cycloheximide inhibited the induction of MnSOD mRNA by OK432. OK432 increased the levels of interleukin-1 (IL-1) and tumor-necrosis-factor-alpha (TNFalpha) mRNA in granulocytes. Furthermore, the induction of MnSOD mRNA by OK432 was blocked by anti-IL-1 antibody but not by anti-TNF antibody. These results suggest that the induction of MnSOD mRNA by OK432 is regulated at the transcriptional level, and OK432 induces MnSOD mRNA, at least in part, through production of IL-1 in granulocytes.