Induction of murine hepatic glutathione S-transferase by dietary dehydroepiandrosterone.

The naturally occurring steroid dehydroepiandrosterone (DHEA), when administered as a supplement to the diet of mice and rats, produces alterations in the relative concentrations of specific liver proteins; among these, a protein of Mr approximately 28 K is markedly induced by DHEA action. In the present study we identified the murine hepatic approximately 28 kDa protein as glutathione S-transferase subtype GT-8.7. Glutathione S-transferases belong to a gene superfamily that encode closely related proteins which are induced in liver and other tissues by various chemicals, including carcinogens and chemoprotective agents such as dietary antioxidants. Based on the above finding, we evaluated glutathione S-transferase activity in cytosols and microsomes prepared from liver tissue of mice fed either a control diet or a DHEA-containing diet (0.45%, by weight). The specific activity of hepatic cytosolic glutathione S-transferase in mice treated with DHEA up to 7 days was either unchanged or slightly decreased when compared to controls; however, treatment for 14 days or longer resulted in significant increases in activity. The specific activity of microsomal glutathione S-transferase also was increased by long-term DHEA treatment; however, its activity was approximately one-tenth of that in corresponding cytosols.

Immunotoxicity of polyunsaturated fatty acids in serum-free medium.

To test the effect of purified polyunsaturated fatty acids on immune cells in vitro, human peripheral blood mononuclear cells and murine spleen cells were incubated in Opti-MEM medium without serum or even albumin and with 2-mercapto-ethanol, insulin, transferrin and selenium as supplements. The human cells were stimulated with phytohemagglutinin and the murine cells were stimulated with Concanavalin A or lipopolysaccharide. Both human and murine cells were stimulated with recombinant human interleukin-2 to generate lymphokine activated killer cells. Linoleic and linolenic acids inhibited all of the immune responses tested, whereas docosahexaenoic and eicosapentaenoic acids did not. Similar effects were observed with cultured B16 F10 murine melanoma cells. Mixtures of linoleic and docosahexaenoic or eicosapentaenoic acids also inhibited the mitogenic response to phytohemagglutinin. Inhibition of lipid mediator production by indomethacin, quercetin, rutin, or nordihydroguariaretic acid, and addition of vitamins C and E with anti-oxidant activity failed to reverse the effects of linoleic acid. Thus, linoleic and linolenic acids appear to directly inhibit immune and tumor cells, at least under these conditions.

Inhibition of pregnancy viability in mice following IL-2 administration.

The influence of administration of interleukin-2 (IL-2) on syngeneic and allogeneic murine pregnancy has been investigated. Human or mouse recombinant IL-2 (rhIL-2 and rmIL-2), or partially purified rat IL-2, was inoculated i.p. into C57B1 mice following syngeneic mating but before embryo implantation. This inhibited subsequent fetal development in up to 100% of cases, compared with mice inoculated with control material, including recombinant human interleukin-1 alpha (IL-1 alpha), where no inhibition of pregnancy viability was observed. Similar data were obtained in both syngeneic and allogeneic matings when rhIL-2 was administered on Day 1 of pregnancy. Administration of rhIL-2 during the second pregnancy, rather than a first pregnancy, was less effective. Administration of rhIL-2 during the first pregnancy does not induce a permanent sterility. Histological examination of the endometrium further demonstrated that mice injected with rhIL-2 on Day 1 of their first pregnancy showed a complete absence of embryonic tissue.

Comparison of immunological changes between subcutaneous and intravenous route of administration of IL-2 in cancer patients.

The effects of the route of administration of interleukin 2 (IL-2) on the immunological parameters of patients with various malignancies were investigated. The percent mean values for IL-2 receptor (Tac) positive cells among mononuclear cells in patients receiving IL-2 subcutaneously (5 cases) or intravenously (6 cases) were 7 and 7%, respectively. The corresponding values of post-IL-2 treatment peak were 18 and 16%. Similarly, the values for class II antigen expressing cells were 12 and 16% and 25 and 26%. In no case the difference between the values for the subcutaneous or the intravenous route reached significance. Using the 51Cr release assay, the mean percent killing activity of IL-2-activated mononuclear cells against Daudi tumour target cells for the subcutaneously and the intravenously treated groups were 27 and 14% and the corresponding values for the post-IL-2 treatment peak were 59% (p > 0.05) and 69% (p > 0.05), respectively. The similar values using K562 tumour as target were 17 and 8%, and the corresponding values for post-treatment peak were 55% (p > 0.05) and 23% (p > 0.05). In all cases the cytotoxic values for the post-IL-2 treatment were significantly greater than the pre-IL-2 values. The mean (+/- SD) values for serum beta2-m levels for 6 subcutaneously and 5 intravenously IL-2-treated patients were 6.5 +/- 4.6 and 5.7 +/- 3.4 mg/l (p > 0.05). The corresponding values for post-IL-2 (15 days) were 9.1 +/- 3.4 and 9.9 +/- 5.1 mg/1, respectively. These results demonstrate that there is no significant difference in the immunological parameters in cancer patients receiving IL-2 via subcutaneous or intravenous routes and provide further support for the current trend for clinical trials to concentrate on outpatients subcutaneous administration.

Studies on cell-mediated immunity in women using different fertility regulating methods.

Cell-mediated immunity (CMI) was assessed in women using fertility regulating methods for 1-5 months, 6-11 months or 12-18 months. The CMI as assessed by phytohaemagglutin in (PHA)-induced lymphocyte transformation of treated groups were compared with that of normal subjects who were not using any contraceptive methods and women on conventional methods of contraception. The data obtained indicates that there is no significant alteration of CMI in women fitted with IUCD or women on estrogen progestogen combination. However, a significant suppression of CMI is observed in women in progestogen pills for 12-18 months. The short term therapy did not affect the CMI. In a prospective study it was found that the CMI in women before and after the use of combination therapy for 1-5 and 6-11 months revealed no change. Estradiol and progesterone at concentration on 1 microgram/ml in culture medium suppressed PHA-induced lymphocyte transformation.