High-Dose Pentoxifylline in Patients with AIDS: Inhibition of Tumor Necrosis Factor Production

Dezube, Bruce J.; Lederman, Michael M.; Spritzler, John; Chapman, Beryl; Korvick, Joyce A.; Flexner, Charles; Dando, Stephen; Mattiacci, M.R.; Ahlers, Christoph M.; Zhang, Lin; Novick, William J.; P, Kasdan; Fahey, John L.; Pardee, Arthur B.; Crumpacker, Clyde S.

doi:10.1093/infdis/171.6.1628

Cited by 44 publications

(16 citation statements)

References 7 publications

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“…Previous studies have shown that PTX, as an effective inhibitor of protein kinase C, protein kinase A and NF-κB, selectively inhibits TNF-α production, as well as HIV-1 transcription and virus production [48],[49]. We show in our study that the parasite-dependent enhancement in HIV-1 production in cocultured cells is no longer seen in presence of PTX.…”

Section: Discussionsupporting

confidence: 41%

Leishmania infantum Amastigotes Enhance HIV-1 Production in Cocultures of Human Dendritic Cells and CD4+ T Cells by Inducing Secretion of IL-6 and TNF-α

et al. 2009

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BackgroundVisceral leishmaniasis has emerged as an important opportunistic disease among patients infected with HIV-1. Both HIV-1 and the protozoan parasite Leishmania can productively infect cells of the macrophage-dendritic cell lineage.Methodology/Principal FindingsHere we demonstrate that Leishmania infantum amastigotes increase HIV-1 production when human primary dendritic cells (DCs) are cocultured together with autologous CD4+ T cells. Interestingly, the promastigote form of the parasite does not modulate virus replication. Moreover, we report that amastigotes promote virus replication in both cell types. Our results indicate that this process is due to secretion of parasite-induced soluble factors by DCs. Luminex micro-beads array system analyses indicate that Leishmania infantum amastigotes induce a higher secretion of several cytokines (i.e. IL-1α, IL-2, IL-6, IL-10 and TNF-α) and chemokines (i.e. MIP-1α, MIP-1β and RANTES) in these cells. Studies conducted with pentoxifylline and neutralizing antibodies revealed that the Leishmania-dependent augmentation in HIV-1 replication is due to a higher secretion of IL-6 and TNF-α.Conclusions/SignificanceAltogether these findings suggest that the presence of Leishmania within DC/T-cell conjugates leads to an enhancement of virus production and demonstrate that HIV-1 and Leishmania can establish complex interactions in such a cellular microenvironment.

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Section: Discussionsupporting

confidence: 41%

Leishmania infantum Amastigotes Enhance HIV-1 Production in Cocultures of Human Dendritic Cells and CD4+ T Cells by Inducing Secretion of IL-6 and TNF-α

et al. 2009

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“…Our results support findings that full immunologic normalization is not achieved during HIV protease inhibitor-based therapy. It may be useful to evaluate therapeutic modalities that down-regulate TNF activity [42][43][44][45] in combination with HAART in HIV-infected patients.…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor (TNF) System Levels in Human Immunodeficiency Virus–Infected Patients during Highly Active Antiretroviral Therapy: Persistent TNF Activation Is Associated with Virologic and Immunologic Treatment Failure

et al. 1999

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Because persistent tumor necrosis factor (TNF)-alpha activation may play a pathogenic role in human immunodeficiency virus infection, TNF component levels were assessed over 78 weeks in plasma and peripheral blood mononuclear cells (PBMC) during highly active antiretroviral therapy (HAART) in 40 HIV-infected patients. HAART induced a significant decline in plasma levels of TNF-alpha and soluble TNF receptors and was associated with a fall in the abnormally increased unstimulated and a rise in the abnormally low Mycobacterium avium complex-purified-protein derivative-stimulated TNF-alpha released from PBMC. However, concentrations of these TNF components were not normalized. Patients with virologic and immunologic treatment failure after 52 weeks had higher levels of several TNF components than other patients early after initiation of therapy, also during periods with adequate virologic response. Although TNF components significantly decreased during HAART, these results support data indicating that full immunologic normalization is not achieved during such therapy. The persistent activation of the TNF system in a subgroup of persons may be involved in treatment failure.

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“…Ibudilast is also currently being tested in clinical trials as a treatment for multiple sclerosis (MS), opioid withdrawal, and neuropathic pain, all of which are conditions involving aberrant microglial activation and CNS inflammation [28], [33], [34]. Other PDE inhibitors, pentoxifylline and rolipram, have been investigated as anti-inflammatory agents, and have been shown to inhibit HIV-1 replication [35], [36], [37]. Because of its approval for use in humans, as well as its ability to cross the blood brain barrier and inhibit glial cell activation, ibudilast is an exciting potential adjunctive therapy for HAND [30].…”

Section: Introductionmentioning

confidence: 99%

Ibudilast, a Pharmacologic Phosphodiesterase Inhibitor, Prevents Human Immunodeficiency Virus-1 Tat-Mediated Activation of Microglial Cells

Kiebala

Maggirwar

2011

PLoS ONE

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Human Immunodeficiency Virus-1 (HIV-1)-associated neurocognitive disorders (HAND) occur, in part, due to the inflammatory response to viral proteins, such as the HIV-1 transactivator of transcription (Tat), in the central nervous system (CNS). Given the need for novel adjunctive therapies for HAND, we hypothesized that ibudilast would inhibit Tat-induced excess production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNFα) in microglial cells. Ibudilast is a non-selective cyclic AMP phosphodiesterase inhibitor that has recently shown promise as a treatment for neuropathic pain via its ability to attenuate glial cell activation. Accordingly, here we demonstrate that pre-treatment of both human and mouse microglial cells with increasing doses of ibudilast inhibited Tat-induced synthesis of TNFα by microglial cells in a manner dependent on serine/threonine protein phosphatase activity. Ibudilast had no effect on Tat-induced p38 MAP kinase activation, and blockade of adenosine A2A receptor activation did not reverse ibudilast's inhibition of Tat-induced TNFα production. Interestingly, ibudilast reduced Tat-mediated transcription of TNFα, via modulation of nuclear factor-kappa B (NF-κB) signaling, as shown by transcriptional activity of NF-κB and analysis of inhibitor of kappa B alpha (IκBα) stability. Together, our findings shed light on the mechanism of ibudilast's inhibition of Tat-induced TNFα production in microglial cells and may implicate ibudilast as a potential novel adjunctive therapy for the management of HAND.

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High-Dose Pentoxifylline in Patients with AIDS: Inhibition of Tumor Necrosis Factor Production

Cited by 44 publications

References 7 publications

Leishmania infantum Amastigotes Enhance HIV-1 Production in Cocultures of Human Dendritic Cells and CD4+ T Cells by Inducing Secretion of IL-6 and TNF-α

Leishmania infantum Amastigotes Enhance HIV-1 Production in Cocultures of Human Dendritic Cells and CD4+ T Cells by Inducing Secretion of IL-6 and TNF-α

Tumor Necrosis Factor (TNF) System Levels in Human Immunodeficiency Virus–Infected Patients during Highly Active Antiretroviral Therapy: Persistent TNF Activation Is Associated with Virologic and Immunologic Treatment Failure

Ibudilast, a Pharmacologic Phosphodiesterase Inhibitor, Prevents Human Immunodeficiency Virus-1 Tat-Mediated Activation of Microglial Cells

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