HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Patel, N. R. Articles by Koziel, H. Search for Related Content PubMed PubMed Citation Articles by Patel, N. R. Articles by Koziel, H.

HIV Impairs TNF- Mediated Macrophage Apoptotic Response to Mycobacterium tuberculosis¹

Naimish R. Patel^2,*, Jinping Zhu^*, Souvenir D. Tachado^*, Jianmin Zhang^*, Zhi Wan, Jussi Saukkonen and Henry Koziel^*

^* Division of Pulmonary, Critical Care and Sleep Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; and Boston Medical Center, Boston University School of Medicine, Boston, MA 02118

The factors that contribute to the exceptionally high incidence of Mycobacterium tuberculosis (MTb) disease in HIV⁺ persons are poorly understood. Macrophage apoptosis represents a critical innate host cell response to control MTb infection and limit disease. In the current study, virulent live or irradiated MTb (iMTbRv) induced apoptosis of differentiated human U937 macrophages in vitro, in part dependent on TNF-. In contrast, apoptosis of differentiated HIV⁺ human U1 macrophages (HIV⁺ U937 subclone) was markedly reduced in response to iMTbRv and associated with significantly reduced TNF- release, whereas apoptosis and TNF- release were intact to TLR-independent stimuli. Furthermore, reduced macrophage apoptosis and TNF- release were independent of MTb phagocytosis. Whereas surface expression of macrophage TLR2 and TLR4 was preserved, IL-1 receptor associated kinase-1 phosphorylation and NF-B nuclear translocation were reduced in HIV⁺ U1 macrophages in response to iMTbRv. These findings were confirmed using clinically relevant human alveolar macrophages (AM) from healthy persons and asymptomatic HIV⁺ persons at clinical risk for MTb infection. Furthermore, in vitro HIV infection of AM from healthy persons reduced both TNF- release and AM apoptosis in response to iMTbRv. These data identify an intrinsic specific defect in a critical macrophage cellular response to MTb that may contribute to disease pathogenesis in HIV⁺ persons.

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 This work was supported by National Institutes of Health Grants NIH R01-HL063655 (to H.K.), NIH Loan Repayment Program (to N.P.), K08-AI064014 (to N.P.), and American Lung Association Biomedical Research Grant (to M.P.). These data were presented in part at the 2004 American Thoracic Society International Meeting, Orlando, FL, and the 2005 American Thoracic Society International Meeting, San Diego, CA.

² Address correspondence and reprint requests to Dr. Naimish Patel, Pulmonary, Critical Care and Sleep Medicine, Beth Israel Deaconess Medical Center, Kirstein Hall, Room KSB-23, 330 Brookline Avenue, Boston, MA 02215. E-mail address: npatel{at}bidmc.harvard.edu

³ Abbreviations used in this paper: MTb, Mycobacterium tuberculosis; IRAK, IL-1 receptor associated kinase; AM, alveolar macrophage; BAL, bronchoalveolar lavage; MOI, multiplicity of infection; RFU, relative fluorescence unit; sTNFR1, soluble TNF receptor 1.

This article has been cited by other articles:

				M. Noursadeghi, J. Tsang, R. F. Miller, and D. R. Katz Comment on "Transcription Factor FOXO3a Mediates Apoptosis in HIV-1-Infected Macrophages" J. Immunol., June 15, 2008; 180(12): 7783 - 7783. [Full Text] [PDF]