POLYSACCHARIDE-K INDUCES MN SUPEROXIDE-DISMUTASE (MN-SOD) IN TUMOR-TISSUES AND INHIBITS MALIGNANT PROGRESSION OF QR-32 TUMOR-CELLS - POSSIBLE ROLES OF INTERFERON-ALPHA, TUMOR-NECROSIS-FACTOR-ALPHA AND TRANSFORMING-GROWTH-FACTOR-BETA IN MN-SOD INDUCTION BY POLYSACCHARIDE-K

Previously we reported the malignant progression of QR-32, a regressor -type tumor clone, following co-implantation with foreign bodies (gela tin sponge or plastic plate) in normal syngeneic C57BL/6 mice. We also reported that the progression of QR-32 cells by a gelatin sponge was significantly inhibited in the mice administered polysaccharide K (PSK ) and that PSK induced an increase of radical scavengers, especially m anganese superoxide dismutase (Mn-SOD), locally at the site of tumor t issues. In this study, to reveal the possible mechanism by which PSK i nduced Mn-SOD in the tumor tissues, we examined the mRNA expression an d protein levels of inflammatory cytokines in the tissues. We found th at mRNAs of tumor necrosis factor alpha (TNF alpha) and interleukin-1 alpha (IL-1 alpha) were considerably expressed in both PSK-treated and phosphate-buffered-saline-treated tumors, and that the mRNA expressio n and protein level of interferon gamma (IFN gamma) increased in the t umor tissues treated with PSK. In vitro treatment of QR-32 cells with IFN gamma did not significantly increase the production of Mn-SOD; how ever, the combination of IFN gamma with TNF alpha increased the Mn-SOD production more effectively than did any of the cytokines used singly . Furthermore, we observed the down-regulation of the mRNA expression and protein level of transforming growth factor beta (TGF beta) in the tumor tissues treated with PSK, and that in vitro treatment of QR-32 cells with TGF beta decreased the production of Mn-SOD. These results suggest that PSK suppresses the progression of QR-32 cells by increasi ng Mn-SOD via the modulation of inflammatory cytokines; that is, by de creasing TGF-beta and increasing IFN-gamma.