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Published ahead of print on August 18, 2005, doi:10.1165/rcmb.2004-0341OC

Am. J. Respir. Cell Mol. Biol., Volume 33, Number 6, December 2005, 610-621

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Submitted on November 3, 2004
Revised on August 17, 2005

HIV Impairs TNF-{alpha} Release in Response to TLR4 Stimulation in Human Macrophages in vitro

Souvenir D Tachado1, Jianmin Zhang1, Jinping Zhu1, Naimish Patel1, and Henry Koziel1*

1 Division of Pulmonary, Critical Care and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA

* To whom correspondence should be addressed. E-mail: hkoziel{at}bidmc.harvard.edu.

The molecular mechanisms for increased risk of bacterial pneumonia in HIV+ persons remain incompletely understood. Recognizing the critical role of 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 ERK1/2 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. Pharmacological 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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