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J. Biol. Chem., Vol. 283, Issue 48, 33191-33198, November 28, 2008

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Constitutive Activation of Phosphatidylinositol 3-Kinase Signaling Pathway Down-regulates TLR4-mediated Tumor Necrosis Factor- Release in Alveolar Macrophages from Asymptomatic HIV-positive Persons in Vitro^*

From the Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

Alveolar macrophages represent critical effector cells of innate immunity to infectious challenge in the lungs and recognize bacterial pathogens through pattern recognition receptors such as Toll-like receptors (TLRs). Phosphatidylinositol 3-kinse (PI3K) regulates TLR-mediated cytokine release, but whether HIV infection influences PI3K signaling pathway and alters TLR4-mediated macrophage response has not been investigated. In the current study, surface TLR4 expression were similar but TLR4 activation (lipid A, 10 µg/ml) resulted in lower TNF- release by HIV+ human macrophages compared with healthy cells. Pharmacological inhibition of PI3K (LY294002) normalized TNF- release in HIV+ macrophages and augments ERK1/2 mitogen-activated protein kinase phosphorylation in response to lipid A. Importantly, HIV+ macrophages demonstrated increased constitutive phosphatidylinositol 3,4,5-trisphosphate formation, increased phosphorylation of downstream signaling molecules Akt and glycogen synthase kinase-3β (GSK-3β) at Ser⁹, and reduced PTEN protein expression. As a functional assessment of GSK-3β phosphorylation, TLR4-mediated interleukin-10 release was significantly higher in HIV+ human macrophages compared with healthy cells. Incubation of human macrophages with exogenous HIV Nef protein induced phosphorylation of Akt and GSK-3β (whereas phosphorylation was reduced by PI3K inhibition) and promoted interleukin-10 release. Taken together, these data demonstrate increased constitutive activation of the PI3K signaling pathway in HIV+ macrophages and support the concept that PI3K activation (by HIV proteins such as Nef) may contribute to reduced TLR4-mediated TNF- release in HIV+ human macrophages and impair host cell response to infectious challenge.

Received for publication, July 2, 2008 , and in revised form, September 25, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01-HL063655 (to H. K.). These data were presented in part at the 2007 American Thoracic Society International Meeting, San Francisco, CA. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Division of Pulmonary, Critical Care and Sleep Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Kirstein Bldg, Rm. KSB-023, Boston, MA 02215. Tel.: 617-667-0053; Fax: 617-667-0149; E-mail: stachado{at}bidmc.harvard.edu.

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