ABSTRACT
BACKGROUND: Chemokines and platelet activation are both important in atherogenesis. Platelet inhibitors are widely used in coronary artery disease (CAD), and we hypothesized that the platelet inhibitor clopidogrel could modify chemokines in CAD patients. OBJECTIVES: We sought to investigate the effect of clopidogrel on the expression of chemokines and chemokine receptors in peripheral blood mononuclear cells (PBMC) in CAD patients. PATIENTS/METHODS: Thirty-seven patients with stable angina were randomized to clopidogrel (n = 18) or placebo (n = 19). PBMC, blood platelets and plasma were collected at baseline and after 7-10 days in the patients, and in 10 healthy controls. mRNA levels of chemokines and chemokine receptors in PBMC were analyzed by ribonuclease protection assays and real-time reverse transcriptase polymerase chain reaction. Platelet activation was studied by flow cytometry. RESULTS: (i) At baseline, the gene expression of the regulated on activation normally T-cell expressed and secreted (RANTES) chemokines and macrophage inflammatory peptide (MIP)-1beta in PBMC, the expression of CD62P and CD63 on platelets and the levels of platelet-derived microparticles (PMP) were elevated in angina patients comparing healthy controls; (ii) markers of platelet activation were either reduced (CD63) or unchanged (CD62P, PMP, beta-thromboglobulin) during clopidogrel therapy; (iii) in contrast, clopidogrel significantly up-regulated the gene expression of RANTES and MIP-1beta in PBMC, while no changes were found in the placebo group; (iv) a stable adenosine 5'-diphosphate metabolite attenuated the release of MIP-1beta, but not of RANTES, from activated PBMC in vitro. CONCLUSIONS: Even if we do not argue against a beneficial role for clopidogrel in CAD, our findings may suggest potential inflammatory effects of clopidogrel in CAD.
Subject(s)
Chemokines/biosynthesis , Coronary Artery Disease/blood , Coronary Artery Disease/drug therapy , Gene Expression Regulation , Leukocytes, Mononuclear/metabolism , Platelet Aggregation Inhibitors/therapeutic use , Ticlopidine/analogs & derivatives , Aged , Cells, Cultured , Clopidogrel , Double-Blind Method , Endothelium, Vascular/metabolism , Female , Humans , Immunoenzyme Techniques , Male , Middle Aged , Placebos , Reverse Transcriptase Polymerase Chain Reaction , Ticlopidine/therapeutic useABSTRACT
To gain further insight into the possible role of interleukin (IL)-18 in HIV-1 infection we examined serum levels of IL-18 in various clinical and immunological stages of HIV-1 infection during cross-sectional (n = 41) and longitudinal testing (n = 20) and during HAART (n = 21, 24 months follow-up). Our main findings were that HIV-1-infected patients had significantly raised IL-18 levels comparing healthy controls, particularly in those with advanced disease, that while HAART induced a marked decline in IL-18, virological treatment failure was associated with persistently raised IL-18 levels during such therapy and that our in vitro experiments showed an IL-18-mediated up-regulation of the HIV-1 coreceptor CXCR4 and the pro-apoptotic mediator TRAIL in PBMC from HIV-1-infected patients receiving HAART. HIV-1 infection appears to be characterized by persistently raised IL-18 levels and during HAART, such a pattern was associated with virological treatment failure, possibly contributing to immunodeficiency and HIV-1 replication in these patients.
Subject(s)
Antiretroviral Therapy, Highly Active , HIV Infections/immunology , HIV-1 , Interleukin-18/blood , Adult , Chemokines/biosynthesis , Chemokines/genetics , Cross-Sectional Studies , Disease Progression , Drug Resistance, Viral/immunology , Female , Gene Expression Regulation/immunology , HIV Infections/drug therapy , Humans , Immune Tolerance , Interleukin-18/immunology , Longitudinal Studies , Male , Middle Aged , RNA, Messenger/genetics , Receptors, Chemokine/biosynthesis , Receptors, Chemokine/genetics , Treatment FailureABSTRACT
BACKGROUND: The pathogenesis of atherosclerosis and acute coronary syndromes involves inflammation and immunological mechanisms. We hypothesized that patients with unstable angina may have an imbalance between inflammatory and anti-inflammatory cytokines. DESIGN: Plasma levels of tumour necrosis factor (TNF)alpha and interleukin (IL)-10 were analyzed in 44 patients with stable angina, 29 patients with unstable angina and 20 controls. mRNA levels of these cytokines were analyzed in peripheral blood mononuclear cells (PBMC). We also studied the in vitro effects of IL-10 in PBMC from unstable angina patients. RESULTS: Our main findings were: (1) the angina patients and particularly those with unstable disease had significantly raised TNFalpha in comparison with the controls, both at the protein and mRNA level; (2) in contrast, the levels of IL-10 were not different in the angina patients in comparison with the healthy controls, resulting in a markedly enhanced TNFalpha:IL-10 ratio, particularly in the unstable angina patients; (3) while exogenously added IL-10 markedly inhibited the release of TNFalpha, IL-8 and tissue factor as well as impairing the gelatinolytic activity and mRNA production of matrix metalloproteinase-9, it enhanced the tissue inhibitor of this metalloproteinase (i.e. TIMP-1) in PBMC from the unstable angina patients. CONCLUSION: Patients with unstable angina appear to have an imbalance between TNFalpha and IL-10, possibly favouring inflammatory net effects. IL-10 may have beneficial effects on mechanisms that are important in plaque rupture and thrombus formation.
