This Article Full Text Full Text (PDF) All Versions of this Article: 2004-0341OCv1 33/6/610    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tachado, S. D. Articles by Koziel, H. Search for Related Content PubMed PubMed Citation Articles by Tachado, S. D. Articles by Koziel, H.

HIV Impairs TNF- Release in Response to Toll-Like Receptor 4 Stimulation in Human Macrophages In Vitro

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

Correspondence and requests for reprints should be addressed to Henry Koziel, M.D., 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. 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 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- release through extracellular regulated kinase (ERK)1/2 mitogen-activated protein (MAP) kinase phosphorylation. In contrast, HIV+ U1 macrophages had significantly reduced TNF- release (despite preserved TLR4 expression) and reduced ERK1/2 phosphorylation, whereas TNF- 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- release and induce MKP-1 in healthy macrophages. Pharmacologic inhibition of endogenous cellular phosphatases increased ERK1/2 phosphorylation and partially restored TLR4-mediated TNF- release in HIV+ macrophages. Furthermore, targeted gene silencing of MKP-1 partially restored lipid A–mediated TNF- 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- 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.

Key Words: alveolar macrophages • innate immunity • MAP kinase • MAP kinase phosphatase-1 • lipid A

This article has been cited by other articles:

				N. R. Patel, J. Zhu, S. D. Tachado, J. Zhang, Z. Wan, J. Saukkonen, and H. Koziel HIV Impairs TNF-{alpha} Mediated Macrophage Apoptotic Response to Mycobacterium tuberculosis J. Immunol., November 15, 2007; 179(10): 6973 - 6980. [Abstract] [Full Text] [PDF]

				S. D. Tachado, J. Zhang, J. Zhu, N. Patel, M. Cushion, and H. Koziel Pneumocystis-mediated IL-8 release by macrophages requires coexpression of mannose receptors and TLR2 J. Leukoc. Biol., January 1, 2007; 81(1): 205 - 211. [Abstract] [Full Text] [PDF]

				Z. Wang, H. Yang, S. D. Tachado, J. E. Capo-Aponte, V. N. Bildin, H. Koziel, and P. S. Reinach Phosphatase-Mediated Crosstalk Control of ERK and p38 MAPK Signaling in Corneal Epithelial Cells Invest. Ophthalmol. Vis. Sci., December 1, 2006; 47(12): 5267 - 5275. [Abstract] [Full Text] [PDF]

				J. W. Du, F. Zhang, J. E. Capo-Aponte, S. D. Tachado, J. Zhang, F.-S. X. Yu, R. A. Sack, H. Koziel, and P. S. Reinach AsialoGM1-Mediated IL-8 Release by Human Corneal Epithelial Cells Requires Coexpression of TLR5 Invest. Ophthalmol. Vis. Sci., November 1, 2006; 47(11): 4810 - 4818. [Abstract] [Full Text] [PDF]