HIV impairs TNF-alpha release in response to Toll-like receptor 4 stimulation in human macrophages in vitro |
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Authors: | Tachado Souvenir D Zhang Jianmin Zhu Jinping Patel Naimish Koziel Henry |
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Institution: | Department of Pulmonary, Critical Care and Sleep Medicine, Kirstein Hall, Room E/KSB-23, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA. |
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Abstract: | The molecular mechanisms for increased risk of bacterial pneumonia in HIV+ persons remain incompletely understood. Recognizing the critical role of Toll-like receptor (TLR) signaling in host defense, this study showed that human U937 macrophage stimulation by the TLR4-specific ligand, lipid A (biologically active component of bacterial LPS), promoted TNF-alpha release through extracellular regulated kinase (ERK)1/2 mitogen-activated protein (MAP) kinase phosphorylation. In contrast, HIV+ U1 macrophages had significantly reduced TNF-alpha release (despite preserved TLR4 expression) and reduced ERK1/2 phosphorylation, whereas TNF-alpha release was intact via a TLR4-independent pathway. In HIV+ U1 cells, reduced ERK1/2 phosphorylation was not due to reduced upstream MEK1/2 activation, but was associated with a reciprocal induction of MAP kinase phosphatase-1 (MKP-1). HIV nef protein was sufficient to reduce TNF-alpha release and induce MKP-1 in healthy macrophages. Pharmacologic inhibition of endogenous cellular phosphatases increased ERK1/2 phosphorylation and partially restored TLR4-mediated TNF-alpha release in HIV+ macrophages. Furthermore, targeted gene silencing of MKP-1 partially restored lipid A-mediated TNF-alpha release in HIV+ U1 cells. Similar results were observed using clinically relevant human alveolar macrophages, comparing healthy to asymptomatic HIV+ persons at clinical risk for bacterial pneumonia. Thus, reduced TLR4-mediated TNF-alpha release through altered ERK1/2 regulation by HIV may impair an effective innate immune response to bacterial challenge. Inhibition of cellular phosphatases may serve as a potential therapeutic target in the management of bacterial pneumonia in HIV+ persons. |
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