Role of IgE immune complexes in the regulation of HIV-1 replication and increased cell death of infected U1 monocytes: involvement of CD23/Fc epsilon RII-mediated nitric oxide and cyclic AMP pathways.

BACKGROUND: IgE/anti-IgE immune complexes (IgE-IC) induce the release of multiple mediators from monocytes/macrophages and the monocytic cell line U937 following the ligation of the low-affinity Fc epsilon receptors (Fc epsilon RII/CD23). These effects are mediated through an accumulation of cAMP and the generation of L-arginine-dependent nitric oxide (NO). Since high IgE levels predict more rapid progression to acquired immunodeficiency syndrome, we attempted to define the effects of IgE-IC on human immunodeficiency virus (HIV) production in monocytes. MATERIALS AND METHODS: Two variants of HIV-1 chronically infected monocytic U1 cells were stimulated with IgE-IC and virus replication was quantified. NO and cAMP involvement was tested through the use of agonistic and antagonistic chemicals of these two pathways. RESULTS: IgE-IC induced p24 production by U1 cells with low-level constitutive expression of HIV-1 mRNAs and extracellular HIV capsid protein p24 levels (U1low), upon their pretreatment with interleukin 4 (IL-4) or IL-13. This effect was due to the crosslinking of CD23, as it was reversed by blocking the IgE binding site on CD23. The IgE-IC effect could also be mimicked by crosslinking of CD23 by a specific monoclonal antibody. p24 induction by IgE-IC was then shown to be due to CD23-mediated stimulation of cAMP, NO, and tumor necrosis factor alpha (TNF alpha) generation. In another variant of U1 cells with > 1 log higher constitutive production of p24 levels (U1high), IgE-IC addition dramatically decreased all cell functions tested and accelerated cell death. This phenomenon was reversed by blocking the nitric oxide generation. CONCLUSIONS: These data point out a regulatory role of IgE-IC on HIV-1 production in monocytic cells, through CD23-mediated stimulation of cAMP and NO pathways. IgE-IC can also stimulate increased cell death in high HIV producing cells through the NO pathway.     

Anti-leukemia Activity of 7-hydroxy-2-substituted-methyl-5 H -oxazolo[3,2- a] pyrimidin-5-one Derivatives

The synthesis of new 7-hydroxy-2-substituted-methyl-5 H -oxazolo[3,2- a] pyrimidin-5-ones derivatives, designed as structural bicyclic analogues of the iron chelator deferiprone, is described. They were tested for their ability to inhibit proliferation in human Bcr-Abl + leukemia cells.     

Rutoside decreases human macrophage-derived inflammatory mediators and improves clinical signs in adjuvant-induced arthritis

Background  

Dietary flavonols may play an important role in the adjunct therapy of chronic inflammation. The availability of therapeutic formulations of pentahydroxyflavone glycoside, rutoside (RU), led us to investigate the ability of this molecule to modulate the release of various proinflammatory mediators from human activated macrophages in vitro and to ameliorate arthritic markers in a rat model.     

Critical role of nitric oxide during the apoptosis of peripheral blood leukocytes from patients with AIDS

BACKGROUND: Highly active antiretroviral therapies (HAART) increase the CD4(+) cell count, but complete normalization of this parameter has not been obtained in some patients. As oxidative stress plays an important role during human immunodeficiency virus type 1 (HIV-1)-associated dementia and lymphocyte apoptosis, we asked whether the nitric oxide (NO) pathway plays a role in the in vitro survival of peripheral blood mononuclear cells (PBMC) from HIV-1(+) patients and how it correlates with peripheral CD4(+) cell levels. MATERIALS AND METHODS: PBMC were isolated from patients with AIDS and assayed for apoptosis and proliferation in the presence of various chemicals, including agonists or antagonists of the NO pathway. Data were then compared with several in vivo parameters from the same patients. RESULTS: Apoptosis of PBMC in the presence of exogenous NO is significantly higher in patients with low peripheral CD4(+) cell levels than in patients with high CD4(+) cell numbers or seronegative individuals. In addition, endogenous NO inhibition rescues cells from apoptosis in AIDS patients with low circulating CD4(+) cell numbers and helps recovery of the T cell proliferative response. NO-mediated apoptosis does not require cGMP but involves peroxynitrite generation, PARP activation, and NAD(+) depletion. CONCLUSIONS: Taken together, the data suggest the involvement of NO during the apoptosis and functional impairment of lymphocytes in patients with AIDS.     

Soluble CD23: cytokine actives on human hematopoietic precursors]

We report herein the effect of soluble CD23 (sCD23) on the differentiation of early lymphoid and myeloid human precursors. CD23 is known as a low affinity receptor for IgE. In addition, our results show that sCD23 in synergy with IL1 has a potent activity on the maturation of prothymocytes and the proliferation of multipotential normal and leukemic myeloid precursors.     

Production by B+ null lymphocytes of an activity increasing the proliferation of T CD4+ lymphocytes in the presence of phytohemagglutinin and IL2

Evidence is presented that B+ null lymphocyte supernatants, previously shown to promote the growth of CD4+ T lymphocyte colonies from human marrow precursors, can also selectively enhance CD4+ T cell proliferative response to PHA and IL2.     

Anti-leukemia activity of 7-hydroxy-2-substituted-methyl-5H-oxazolo[3,2-a]pyrimidin-5-one derivatives

The synthesis of new 7-hydroxy-2-substituted-methyl-5H-oxazolo[3,2-a]pyrimidin-5-ones derivatives, designed as structural bicyclic analogues of the iron chelator deferiprone, is described. They were tested for their ability to inhibit proliferation in human Bcr-Abl+ leukemia cells.     

Synthesis and preliminary evaluation of new ursolic and oleanolic acids derivatives as antileishmanial agents

A series of new ursolic and oleanolic acids derivatives was synthesized via ursolic or oleanolic acids, previously extracted from South American Ilex species. These new compounds were tested for in vitro antiparasitic activity on Leishmania amazonensis and Leishmania infantum strains. Some of these compounds showed activity against the promastigote forms of L. amazonensis or L. infantum, with IC₅₀ ranging from 5 to 12 μM. As expected, most of the compounds showed a significant level of cytotoxicity against monocytes (IC₅₀ = 2-50 μM). From a structure-activity relationships point of view, these pharmacological results enlightened mainly the importance of an acetylation at position 3 of the oleanolic acid skeleton in the activity against the L. amazonensis strain, and of a bis-(3-aminopropyl)piperazine moiety on the carboxylic function of ursolic acid against the L. infantum strain.     

Synthesis and evaluation of the antiproliferative activity of novel isoindolo[2,1-a]quinoxaline and indolo[1,2-a]quinoxaline derivatives

A novel series of isoindolo[2,1-a]quinoxaline and indolo[1,2-a]quinoxaline derivatives was synthesized and evaluated in vitro against various human cancer cell lines for antiproliferative activity. These new compounds displayed activity against leukemia and breast cancer cell lines in the 3- to 18-μM concentration range.