Yuejian Wang

In vivo and in vitro cocaine modulation on production of cytokines in C57BL/6 mice.

In the present study we used both in vivo and in vitro murine models to investigate the effects of cocaine on the release of cytokines (IL-1 alpha, IL-6, and TNF-alpha by peritoneal macrophages and splenocytes, IL-2, IL-4, IL-5, IL-10, and IFN-gamma produced by splenocytes. In vitro cocaine (0.1, 1, 10, 100 micrograms/ml) exposure inhibited all cytokines produced by ConA-stimulated spleen cells and LPS-stimulated macrophages in a concentration dependent manner. Different effects of cocaine administration on cytokine production were observed when female C57BL/6 mice were injected intraperitoneally with cocaine (40 mg/kg body weight for six weeks). Secretion of IL-2 by splenocytes was significantly enhanced by cocaine administration, whereas IFN-gamma was not affected. Secretion of IL-4 and IL-10 by splenocytes was significantly inhibited by cocaine administration, while secretion of IL-5 by splenocytes was significantly enhanced. Secretion of IL-6 and TNF-alpha by splenocytes was significantly enhanced by cocaine administration. Secretion of IL-6 by peritoneal macrophages was also significantly enhanced by the cocaine, while production of IL-1 alpha was not affected. However, release of TNF-alpha by peritoneal macrophages was significantly reduced by the cocaine administration. Therefore use of cocaine may alter the balance of cytokine production, and thereby adversely affects immune response and host defense.

Modulation of immune function and cytokine production by various levels of vitamin E supplementation during murine AIDS

Female C57BL/6 mice were infected with LP-BM5 retrovirus, causing murine AIDS which is functionally similar to human AIDS. Dietary supplementation, with a 15-, 150- and 450-fold increase of vitamin E in a liquid diet, significantly restored levels of interleukin-2 (IL) and interferon-gamma produced by splenocytes, which were suppressed by retrovirus infection. Retrovirus infection elevated levels of IL-6 and IL-10 produced by splenocytes, which were significantly normalized by all levels of vitamin E supplementation, respectively. Increased levels of IL-6 and tumor necrosis factor-alpha, produced by splenocytes during progression to murine AIDS, were also significantly normalized by all levels of vitamin E supplementation. Vitamin E supplementation restored retrovirus-suppressed splenocyte proliferation and natural killer cell cytotoxicity. Vitamin E supplementation also alleviated the AIDS symptoms: splenomegaly and hypergammaglobulinemia. These data indicate that dietary vitamin E supplementation at extremely high levels was not immunotoxic, and can modulate cytokine release and normalize immune dysfunctions during progression to murine AIDS. It should favorably affect host resistance and thereby retard the development of AIDS.

Is alcohol consumption a cofactor in the development of acquired immunodeficiency syndrome

Excessive alcohol (EtOH) consumption and acquired immunodeficiency syndrome (AIDS) are two major public health problems in the United States. Overwhelming evidence is showing that heavy EtOH ingestion broadly suppresses the various arms of immune response, seriously impairing the bodys normal host defense to invading microbes and tumorigenesis. The onset of clinical symptoms of AIDS (low CD4+ T cells count, opportunistic infections, and tumors) is quite variable among HIV+ individuals with a mean incubation time 3-10 years following seroconversion. Because of the deleterious effects of chronic EtOH consumption on cytokine release, immune response, host defense, nutritional status, and oxidative stress, it has been believed to be a possible cofactor that could enhance the hosts susceptibility to infections, and subsequently increase the rate of AIDS development. The purpose of this review is to present evidence indicating clinical disorders during EtOH ingestion in murine AIDS. These EtOH-induced abnormalities may promote a more rapid development of AIDS in HIV-infected individuals.

Modification of thymic cell subsets induced by long-term cocaine administration during a murine retroviral infection producing AIDS

LP-BM5 murine leukemia virus (MuLV) infection and cocaine administration are known to impair the murine immune system. We have developed a murine model to study the effect of daily cocaine administration and retrovirus infection on the lymphoid cell populations of the thymus. C57BL/6 female mice were studied following chronic cocaine administration for 11 weeks with simultaneous LP-BM5 MuLV infection. Cocaine administration reduced body and thymus weight, significantly reduced the number of CD8+ cells in the thymus, and partially prevented thymus enlargement due to lymphoid cell proliferation induced by LP-BM5 MuLV infection. Retrovirus infection was associated with a decrease in the percentage and absolute number of Thy 1.2+, CD4+, and CD8+ cells in the thymus, an effect potentiated by cocaine administration. Therefore cocaine impairs thymic function by altering the number of cells expressing T cell differentiation markers in MAIDS.

Suppression of tissue levels of vitamin A, E, zinc and copper in murine aids*

Abstract Female C57BL/6 mice were infected with LP-BM5 retrovirus, causing murine acquired immune deficiency syndrome (MAIDS) which is functionally similar to human AIDS. Because human immunodeficiency virus may compromise nutritional status and nutritional disorders have been found in AIDS patients, the influence of murine retrovirus infection on levels of important immune-related nutrients (vitamin A, E, zinc and copper) in the serum, liver, small intestine, spleen and thymus was determined in MAIDS. The levels of vitamin A, E and copper in the liver in MAIDS were significantly reduced compared to controls, whereas the level of zinc in the liver was not affected. Intestinal level of vitamin A was significantly reduced by retrovirus infection, whereas copper level in the small intestine was significantly increased compared to controls. Intestinal levels of zinc and vitamin E were not affected. The levels of vitamin A, E and zinc in the spleen in murine AIDS were significantly rebared compared to controls, whereas the splenic level of copper was not influenced. The levels of vitamin A, E and copper in the thymus in MAIDS were significantly lessened by retrovirus infection compared to controls, whereas thymic level of zinc was significantly elevated. The levels of vitamin A and E in the serum in MAIDS were significantly decreased by retrovirus infection compared to controls. The data indicated that retrovirus infection can directly cause malnutrition, possible via damaging gastrointestinal cells, thereby leading to malabsorption. Such malnutrition has the theoretical potential to accelerate development of AIDS via immunosuppression secondary to nutritional deficiency.

Potential therapeutics of vitamin E (tocopherol) in AIDS and HIV.

Acquired immune deficiency syndrome (AIDS) is a clinical disorder caused by a retrovirus infection. It represents the end point in a progressive sequence of immunosuppressive changes. Human immunodeficiency virus (HIV), the key causative agent of AIDS, induces immunosuppression and results in host defense defects that render the body highly susceptible to opportunistic infections and neoplasiaJI] AIDS has been identified as a major public health priority in the world with heavy social and economic effects. Because of the unique pathogenicity of HI V, the long latent period of HI V infection and its infectiousness, the size of the AIDS epidemic has steadily increased in recent years. Therefore, there is a pressing need for effective therapeutic and palliative interventions in individuals carrying the virus. The pathogenic mechanisms underlying HIV infection and AIDS are not unidimensional. They are extremely complex and include cytokine dysregulation, immune dysfunction, nutritional disorder and oxidative stress.£2-7] Thus, a comprehensive therapeutic strategy including nutritional therapy for patients with HIV or AIDS might retard the development of the disease more than does any currently available single agent. New strategies such as specific nutrient supplementation should provide additional approaches to improve nutritional status and ameliorate immune dysfunction in patients with HIV, eventually slowing the progression of the disease to AIDS. One of the most attractive nutrients in this respect is vitamin E (tocopherol), an antioxidant, free radical scavenger and immunoenhancer. Vitamin E is a widely distributed, fat-soluble vitamin composed of several tocopherols and tocotrienols, the most biologically active of which is (X-tocopherol.£8] (X-Tocopherol is the principal lipid-soluble, chain-breaking antioxidant, protecting cell plasma membranes and lipoproteins from peroxidative damage.[9,1O] Consequently, the combination of existing medical therapy with vitamin E supplementation may provide a successful and novel therapeutic approach for treatment of patients with HIVor AIDS. However, most of the research in AIDS therapy has focused on how HIV affects the immune system and in developing drugs to inhibit virus replication. No clinical trial has been performed regarding the therapeutic role of vitamin E in patients with HIV or AIDS. This article reviews vitamin E-related therapeutic roles in cytokine production, immune response, oxidative stress and nutritional status in humans and animal models. It supports the concept that vitamin E supplementation could be used therapeutically to treat AIDS.

Chronic ethanol consumption prior to retrovirus infection alters cytokine production by thymocytes during murine AIDS

Chronic ethanol (EtOH) consumption may be a cofactor in the development of acquired immune deficiency syndrome (AIDS). As the thymus is an unique site for T cell maturation, we investigated whether thymocytes from EtOH consuming mice were more predisposed to aberrant cytokine production due to retrovirus infection. Adult female C57BL/6 mice were fed 4.5% (v/v) in liquid diet or control liquid diet without EtOH for 10 weeks. All diets contained nutrients at only the recommended daily intake level for mice. Then all mice were infected LP-BM5 retrovirus and were fed control liquid diets without EtOH. The body and thymus weights were not affected by EtOH consumption. However, thymocyte number and proliferation, which had been reduced during murine AIDS, were significantly further reduced by EtOH use. The production of IL-2 and IL-6 by thymocytes, which was lessened during retrovirus infection, were significantly further suppressed by dietary EtOH at 6 weeks postinfection, whereas levels of IL-4 and IFN-gamma by thymocytes, which were elevated during retrovirus infection, were significantly and slightly further increased by EtOH-treated mice prior to retrovirus infection, respectively. These data suggest that dietary EtOH consumption can modulate cytokine production by thymocytes, adversely affecting T cell differentiation, especially during retrovirus infection. These results provide additional evidence that EtOH consumption should be a cofactor during development of AIDS via producing altered cytokine production and then disrupting T cell differentiation.

Modification of spleen cell subsets by chronic cocaine administration and murine retrovirus infection in normal and protein-malnourished mice.

We have developed an experimental mouse model to study the effect of daily cocaine administration on the immune system during an acquired immune deficiency syndrome (AIDS). Mice were infected with LP-BM5 murine leukemia virus, a retrovirus which causes immunosuppression with the development of functional murine AIDS. Increasing doses of cocaine given by daily intraperitoneal injection for 11 weeks reduced body weight. A daily cocaine injection in some mice as well as a saline injection in others showed a decrease in the percentage of Thy 1.2+, CD4+ and CD8+ cells, while both treatments increased the percentage and absolute numbers of B-cells per spleen. Saline and cocaine treatment induced an increase in gamma-IFN and TNF-alpha production by splenocytes. Cocaine treatment favored a decrease in sIL-2R secretion. Saline and cocaine treatment had slightly different effects on the splenocytes of protein-malnourished mice. Cocaine treatment induced an increase in the percentage of CD8+ cells. Saline and cocaine treatments decreased the number of Mac 1+ cells in the spleen. Moreover, saline- and cocaine-treated protein-malnourished mice splenocytes did not present the increase in gamma-IFN production as well-nourished mice splenocytes showed. Retrovirus-infected mice showed a decrease in the percentage of Thy 1.2+ and CD8+ cells and an increase in the percentage and absolute numbers of CD4+, IL-2R+, Mac 1+ and B-cells. Cocaine partially prevented the enlargement of lymphoid organs due to lymphoid cell proliferation induced by murine retrovirus infection, but had little effect on the elevated percentage of CD4+ cells or B-cells or the depressed numbers of CD8+ cells associated with virus infection. However, cocaine did reduce the number of activated IL-2R+ cells and macrophages (Mac 1+) in addition to reducing the total number of cells per spleen in all subsets in retrovirus-infected mice, but not in uninfected controls. Cocaine treatment and retrovirus infection alone or in combination suppressed the release of sIL-2R into supernatant fluid during in vitro culture of splenocytes. These data illustrate that cocaine treatment modulates cell proliferation in retrovirus-infected mice and thus modifies the absolute number of cells in those subsets already altered by retrovirus infection. Retrovirus-infected and retrovirus-infected cocaine-treated protein-malnourished mice showed similar results.

Normalization of nutritional status by various levels of vitamin E supplementation during murine AIDS

Abstract Female C57BL/6 mice were infected with LP-BM5 retrovirus, causing murine AIDS which is functionally similar to human AIDS. Dietary supplementation, with a 15-, 150- and 450-fold increase of vitamin E in a liquid diet (National Council Research), significantly restored serum and haptic vitamin A and E which had been reduced by retrovirus infection. They also significantly restored hepatic copper, which had been reduced by retrovirus infection, whereas only 150- and 450-fold vitamin E improved hepatic zinc level. Vitamin E supplementation at all levels had no effects on hepatic zinc and copper levels in normal mice, whereas they significantly increased serum and hepatic vitamin A and E concentrations. Vitamin E supplementation at all levels significantly increased intestinal vitamin A and E levels during murine AIDS, whereas only intestinal vitamin E levels was altered by various levels of vitamin E supplementation. Interestingly, vitamin E supplementation had no effect on intestinal copper level, whereas they significantly increased intestinal zinc level in the normal mice and only 450-fold vitamin E supplementation significantly elevated intestinal level of zinc. These data indicate that dietary vitamin E supplementation at extremely high levels was not toxic, can improve undernutrition initiated by retrovirus infection during progression to murine AIDS, which should favorably affect immune response.

Vitamin E supplementation modulates cytokine production by thymocytes during murine AIDS

Female C57BL/6 mice were infected with LP-BM5 retrovirus, causing murine AIDS, which is functionally similar to human AIDS. Retrovirus infection targeted the thymus, producing altered T cell differentiation via the dysregulation of thymocyte cytokine production. Human AIDS causes vitamin deficiencies, therefore the effects of dietary vitamin E supplementation were determined on the kinetics of cytokine production by concanavalin A-stimulated thymocytes in uninfected normal mice and mice with murine AIDS. Dietary supplementation, with a 15-fold increase in vitamin E (160 IU/1) in the liquid diet (National Research Council), modulated interleukin-2 (IL) production in both uninfected mice and retrovirus-infected mice. Vitamin E significantly reduced the level of IL-4 secretion in the uninfected mice at 4 and 8 weeks, but not at 12 and 16 weeks. It also significantly reduced IL-4 production, elevated by retrovirus infection. Vitamin E significantly reduced IL-6, and interferon-γ production increased in murine AIDS. The effects of dietary vitamin E on concanavalin A-induced proliferation of thymocytes were consistent with the finding of changes in IL-2 secretion. No effects of dietary vitamin E on thymus weight were observed in uninfected or retrovirus-infected mice, whereas vitamin E significantly increased serum and thymic vitamin E concentration, which had been reduced by retrovirus infection. These data indicate that dietary vitamin E supplementation can modulate cytokine production by thymocytes, affecting T cell differentiation, especially during retrovirus-induced immune dysfunction.