prostaglandin-d2 and Acquired-Immunodeficiency-Syndrome

Regulation of cytokine and chemokine expression in microglia may have implications for CNS inflammatory disorders. In this study we examined the role of the cyclopentenone PG 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) in microglial inflammatory activation in primary cultures of human fetal microglia. 15d-PGJ(2) potently inhibited the expression of microglial cytokines (IL-1, TNF-alpha, and IL-6). We found that 15d-PGJ(2) had differential effects on the expression of two alpha-chemokines; whereas the Glu-Lys-Arg (ELR)(-) chemokine IFN-inducible protein-10/CXCL10 was inhibited, the ELR(+) chemokine IL-8/CXCL8 was not inhibited. These findings were shown in primary human microglia and the human monocytic cells line THP-1 cells, using diverse cell stimuli such as bacterial endotoxin, proinflammatory cytokines (IL-1 and TNF-alpha), IFN-beta, and HIV-1. Furthermore, IL-8/CXCL8 expression was induced by 15d-PGJ(2) alone or in combination with TNF-alpha or HIV-1. Combined results from EMSA, Western blot analysis, and immunocytochemistry showed that 15d-PGJ(2) inhibited NF-kappaB, Stat1, and p38 MAPK activation in microglia. Adenoviral transduction of super-repressor IkappaBalpha, dominant negative MKK6, and dominant negative Ras demonstrated that NF-kappaB and p38 MAPK were involved in LPS-induced IFN-inducible protein 10/CXCL10 production. Interestingly, although LPS-induced IL-8/CXCL8 was dependent on NF-kappaB, the baseline or 15d-PGJ(2)-mediated IL-8/CXCL8 production was NF-kappaB independent. Our results demonstrate that 15d-PGJ(2) has opposing effects on the expression of two alpha-chemokines. These data may have implications for CNS inflammatory diseases.

Topics: Acquired Immunodeficiency Syndrome; Chemokine CXCL10; Chemokines, CXC; DNA-Binding Proteins; Gene Expression Regulation; HIV-1; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-1; Interleukin-8; Microglia; Mitogen-Activated Protein Kinases; NF-kappa B; Prostaglandin D2; STAT1 Transcription Factor; Trans-Activators; Tumor Necrosis Factor-alpha

Metabolic disorders in HIV-infected patients, especially those receiving highly active antiretroviral therapy (HAART) regimens containing protease inhibitors, are associated with insulin resistance. These metabolic disorders include fat redistribution, diabetes, and hypertriglyceridemia. Thiazolidinediones (TZDs) are used to treat patients with diabetes secondary to insulin resistance, and TZDs are being studied in HAART-related metabolic disorders. We studied the effects of TZDs (peroxisome proliferator-activated receptor-gamma [PPARgamma] agonists) and a PPARalpha agonist on HIV replication and TNFalpha production in peripheral blood mononuclear cells (PBMCs) acutely infected with HIV-1, in a chronically infected monoblastoid cell line (U1) and in alveolar macrophages (AMs) from HIV-infected subjects and uninfected controls. Rosiglitazone, ciglitazone, troglitazone, and PgJ (PPARgamma agonists) as well as fenofibrate (PPARalpha agonist) inhibited HIV replication in both PBMCs and U1 cells. These agents also inhibited TNFalpha production, but the magnitude of TNFalpha inhibition was not directly correlated with the quantitative decreases in HIV replication. In AMs, ciglitazone, rosiglitazone, and troglitazone reduced TNFalpha production. We hypothesize that alterations in mitogen-activated protein kinase signaling pathways have contemporaneous and interrelated effects on HIV replication, cytokine production, and lipid metabolism. Modulation of these pathways using PPAR agonists may improve the metabolic alterations during HAART in conjunction with desirable decreases in HIV replication and TNFalpha production.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Cell Line; Chromans; Fenofibrate; HIV-1; Humans; Leukocytes, Mononuclear; Macrophages, Alveolar; Prostaglandin D2; Receptors, Cytoplasmic and Nuclear; Rosiglitazone; Thiazoles; Thiazolidinediones; Transcription Factors; Troglitazone; Tumor Necrosis Factor-alpha; Virus Replication

To explain a possible pathogenesis of acquired immune deficiency syndrome (AIDS) in homosexual males, we propose the following hypothesis. Prostaglandin E2 in human semen given via anus during anal intercourse may cause an immune dysregulation in the male semen recipients; this immunosuppressive effect of prostaglandin E2 may be one of the underlying factors that stimulate AIDS-associated virus infection or that trigger the latent AIDS-associated virus. This hypothesis is supported by the following experimental results. Anal infusion of prostaglandin E2 or D2 into male rats reduced in vitro responses of T lymphocytes to phytohemagglutinin. However, the T-cell response of female rats was not reduced significantly by the anal infusion of seminal prostaglandins.

Topics: Acquired Immunodeficiency Syndrome; Anal Canal; Animals; Dinoprost; Dinoprostone; Female; Immunity, Cellular; Immunosuppression Therapy; Lymphocyte Activation; Male; Phytohemagglutinins; Prostaglandin D2; Prostaglandins D; Prostaglandins E; Prostaglandins F; Rats; Sex Factors