Massive loss of skeletal muscle mass (cachexia) is sign of HIV infection, sepsis, and trauma, and a cause of death among cancer patients. In HIV infection, the immunological dysfunction develops progressively into a severe condition called acquired immunodeficiency syndrome. Increasing evidence suggests that an abnormal cysteine and glutathione metabolism plays a decisive role in the development of catabolic conditions and associated immunological dysfunctions. This chapter gives a conceptual overview; the chances for a therapeutic intervention with cysteine derivatives such as N-acetylcysteine (NAC) and the methodological aspects. The agenda is to identify abnormal biochemical patterns in different catabolic diseases and conditions, abnormal biochemical parameters that are significantly correlated with mortality, disease progression, and weight loss, to prove cause-and-effect relationships by experimental intervention, to develop and optimize interventive strategies that may be suitable for clinical therapy, and to test new therapeutic strategies in clinical trials. Discussed are the elevated venous plasma glutamate levels as universal marker for catabolic and precatabolic conditions—evidences for an impairment of muscular membrane transport activities, abnormal cysteine catabolism and glutathione level in skeletal muscle tissue, and the pathological significance of decreased membrane transport activity and elevated venous plasma glutamate levels. There is discussion on “Push” and “Pull” mechanisms in catabolic and precatabolic processes, decreased plasma cystine levels and evidence for “Push” and “Pull” mechanisms in sepsis, HIV Infection, and other malignant diseases, abnormally low plasma cystine and glutamine levels in patients with chronic fatigue syndrome (CFS), and the hypothetical mechanism of the “pull” condition—evidence for an abnormal cysteine and glutathione metabolism in liver. Noted are the immunological implications—cysteine deficiency and immunological dysfunction, abnormal glutathione levels in HIV Infection, and redox regulation by glutathione and glutathione disulfide. Also, there are details on the therapeutic intervention with a cysteine derivative: effects of long-term treatment with N-acetylcysteine.

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 inter‐leukin‐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 γ‐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. FASEB J. 10, 1219‐1226 (1996)

Publisher Summary Interest in the role of thiols in the immune system was originally focused on the need to optimize lymphocyte cultures for studying other regulatory components of the immune system in vitro . This chapter describes some experimental approaches that are being used to determine the role of cysteine and cysteine derivatives in the immune system. The chapter evaluates the therapeutic effects and potential side effects of cysteine derivatives. The T cell system is profoundly influenced even by relatively moderate changes in the extracellular cysteine concentration and the intracellular glutathione and glutathione disulfide levels. The limiting role of cysteine is mainly the consequence of the weak cystine transport activity of lymphocytes and the relatively low extracellular concentrations of reduced cysteine in blood plasma or cell cultures. Activated macrophages have been shown to deliver substantial amounts of reduced cysteine and to increase the intracellular glutathione levels of activated T cells in their vicinity.

Patienten mit fortgeschrittenen Tumoren leiden vielfach unter einem fortschreitenden Verlust an Körperzellmasse (Kachexie), der für einen hohen Prozentsatz dieser Patienten als eigentliche Todesursache angesehen werden kann (Heymsfield et al. 1982; Grunfeld 1991). Außerdem zeigen Krebspatienten vielfach eine verminderte immunologische Reaktivität und eine damit verbundene erhöhte Gefährdung durch lebensbedrohende Infektionen (Nixon et al. 1988; Arbeit et al. 1984; Dröge et al. 1988a, b; Richner et al. 1991). Die Kombination von progressiver Kachexie und verminderter immunologischer Reaktivität findet sich auch bei anderen Erkrankungen mit völlig unterschiedlicher Ätiologie, wie z. B. bei der HIV-Infektion (Kotler et al. 1985, 1989, 1991; Rosenberg u. Fauci 1989). Die Mechanismen dieser immunpathologischen und kachektischen Prozesse sind noch nicht im Detail bekannt. In beiden Fällen aber, d. h. sowohl bei Kresberkrankungen als auch bei HIV-Infektionen, ist ein erhöhter Plasma-Glutamat-Spiegel festgestellt worden (Dröge et al. 1988a, b; Eck et al. 1989b). Der vorliegende Bericht beschreibt die Zusammenhänge zwischen der erhöhten extrazellulären Glutamatkonzentration und der Zysteinversorgung bzw. dem intrazellulären Glutathionspiegel.

Publisher Summary The importance of thiols and especially of cysteine and glutathione to lymphocyte function has been known for several years. The extracellular concentrations of thiols have a profound effect on B and T cell responses in vitro . There are also strong indications that cyst(e)ine may play a limiting role for the immune system in vivo . Certain lymphocyte functions, however, are potentiated by hydrogen peroxide or other reactive oxygen intermediates. The intact immune system thus appears to require a delicate balance between prooxidant and antioxidant conditions. This is maintained by a limited and well-regulated supply of cysteine. The pathological changes in cellular cysteine supply that are seen in persons infected with the human immunodeficiency virus (HIV) are associated with an immunological disorder. This chapter describes several experimental approaches that are being used to determine the intracellular concentrations, redox states, the functions of cysteine and glutathione, and the role of functionally related metabolites.

Bone marrow-derived macrophages (BMMPHI) were shown before to function as antigen-presenting cells.We show here, that the antigen presentation capacity of BMMPHI 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 BMMPHI treated with GM-CSF (GM-CSF-MPHI) were efficient presenters, but when presentation of the antigens ovalbumin and conalbumin was tested, IFN-gamma-pulsed BMMPHI (IFN-gamma-MPHI) proved superior to GM-CSF-MPHI. The lack of efficient BI presentation function of IFN-gamma-MPHI was only obvious, when native BI was used as antigen. Preprocessed BI was presented by IFN-gamma-MPHI with drastically higher efficiency than by GM-CSF-MPHI. Because processing of insulin depends on reduction of disulfide bonds, we analyzed the content of intracellular reducing thiols within IFN-gamma-MPHI, GM-CSF-MPHI, and untreated BMMPHI. 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 BMMPHI 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.