Abnormal glutathione and sulfate levels after interleukin 6 treatment and in tumor-induced cachexia.

Excessive urea excretion associated with a negative nitrogen balance and massive loss of skeletal muscle mass (cachexia) is a frequent life threatening complication in malignancies and HIV infection. As these patients have often elevated interleukin-6 (IL-6) and abnormally low cystine levels, we have now determined the intracellular levels of glutathione and other cysteine derivatives in the liver and muscle tissue of IL-6-treated or tumor-bearing C57BL/6 mice. IL-6 treatment or inoculation of the MCA-105 fibrosarcoma caused a significant increase in hepatic gamma-glutamyl-cysteine synthetase activity and a decrease in the sulfate level, glutamine/urea ratio, and glutamine/glutamate ratio, suggesting that a decrease of the proton generating cysteine catabolism in the liver may increase carbamoyl-phosphate synthesis and urea formation at the expense of net glutamine synthesis. Treatment with cysteine, conversely, caused an increase in sulfate, glutamine/urea ratios, and glutamine/glutamate ratios and may thus be a useful therapeutic tool in clinical medicine. In contrast to the liver, muscle tissue of tumor-bearing mice showed decreased glutathione and increased sulfate levels, suggesting that the cysteine pool may be drained by an increased cysteine catabolism in this tissue. The findings indicate that tumor cachexia is triggered initially by IL-6 and is later sustained by processes driven by an abnormal cysteine metabolism in different organs.-Hack, V., Gross, A., Kinscherf, R., Bockstette, M., Fiers, W., Berke, G., and Dröge, W. Abnormal glutathione and sulfate levels after interleukin 6 treatment and in tumor-induced cachexia.

The efficient bovine insulin presentation capacity of bone marrow-derived macrophages activated by granulocyte-macrophage colony-stimulating factor correlates with a high level of intracellular reducing thiols.

Bone marrow-derived macrophages (BMM phi) were shown before to function as antigen-presenting cells. We show here, that the antigen presentation capacity of BMM phi depends on the nature of the antigen and is differently regulated by the lymphokines interferon-gamma (IFN-gamma) and granulocyte/macrophage-colony-stimulating factor (GM-CSF). When bovine insulin (BI) was employed as antigen, only BMM phi treated with GM-CSF (GM-CSF-M phi) were efficient presenters, but when presentation of the antigens ovalbumin and conalbumin was tested, IFN-gamma-pulsed BMM phi (IFN-gamma-M phi) proved superior to GM-CSF-M phi. The lack of efficient BI presentation function of IFN-gamma-M phi was only obvious, when native BI was used as antigen. Preprocessed BI was presented by IFN-gamma-M phi with drastically higher efficiency than by GM-CSF-M phi. Because processing of insulin depends on reduction of disulfide bonds, we analyzed the content of intracellular reducing thiols within IFN-gamma-M phi, GM-CSF-M phi, and untreated BMM phi. Only after stimulation with GM-CSF did the amount of reduced glutathione and cysteine strongly increase, while IFN-gamma did not efficiently augment the intracellular content of both thiols. These findings suggest that the lymphokines IFN-gamma and GM-CSF differently interfere with the processing capacity of BMM phi by differently regulating the intracellular concentration of the thiols reduced glutathione and cysteine. A high level of these thiols induced by GM-CSF correlates with a prominent capacity to present the antigen bovine insulin.