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

Published online before print August 4, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: jlb.0105056v1 78/4/1016    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 Lee, C. Articles by Collman, R. G. Search for Related Content PubMed PubMed Citation Articles by Lee, C. Articles by Collman, R. G.

(Journal of Leukocyte Biology. 2005;78:1016-1023.)
© 2005 by Society for Leukocyte Biology

HIV-1 gp120-induced TNF- production by primary human macrophages is mediated by phosphatidylinositol-3 (PI-3) kinase and mitogen-activated protein (MAP) kinase pathways

Chuhee Lee^*, Brian Tomkowicz^*, Bruce D. Freedman and Ronald G. Collman^*,1

^* Departments of Medicine, University of Pennsylvania School of Medicine, and
Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia

¹Correspondence: University of Pennsylvania School of Medicine, 522 Johnson Pavilion, 36th & Hamilton Walk, Philadelphia, PA 19104. E-mail: collmanr{at}mail.med.upenn.edu

Human immunodeficiency virus type 1 (HIV-1) infection is initiated by binding of the viral envelope glycoprotein gp120 to CD4 followed by a chemokine receptor, but these interactions may also take place independently from infection. gp120 stimulation of primary human macrophages is known to trigger production of cytokines implicated in pathogenesis, particularly tumor necrosis factor (TNF-), but the mechanisms have not been determined. We sought to define the pathways responsible for TNF- secretion by monocyte-derived macrophages (MDM) following HIV-1 gp120 stimulation. MDM exposure to recombinant macrophage-tropic (R5) gp120 led to dose- and donor-dependent release of TNF-, which was cyclohexamide-sensitive and associated with up-regulated message. Pretreatment with specific inhibitors of the mitogen-activated protein kinases (MAPK) extracellular signal-regulated kinase 1/2 (ERK-1/2; PD98059, U0126) and p38 (SB202190, PD169316) inhibited the secretion of TNF-. gp120-elicited TNF- production was also blocked by phosphatidylinositol-3 kinase (PI-3K) inhibitors (wortmannin, LY294002). Moreover, PI-3K inhibition ablated gp120-induced phosphorylation of p38 and ERK-1/2. The response was inhibited by a CC chemokine receptor 5 (CCR5)-specific antagonist, indicating that CCR5 was in large part responsible. These results indicate that gp120-elicited TNF- production by macrophages involves chemokine receptor-mediated PI-3K and MAPK activation, that PI-3K is an upstream regulator of MAPK in this pathway, and that p38 and ERK-1/2 independently regulate TNF- production. These gp120-triggered signaling pathways may be responsible for inappropriate production of proinflammatory cytokines by macrophages, which are believed to play a role in immunopathogenesis and in neurological sequelae of AIDS.

Key Words: monocyte • AIDS • signal transduction • HIV-associated dementia

This article has been cited by other articles:

				M. Malik, Y.-Y. Chen, M. F. Kienzle, B. E. Tomkowicz, R. G. Collman, and A. Ptasznik Monocyte Migration and LFA-1-Mediated Attachment to Brain Microvascular Endothelia Is Regulated by SDF-1{alpha} through Lyn Kinase J. Immunol., October 1, 2008; 181(7): 4632 - 4637. [Abstract] [Full Text] [PDF]

				R. Cheung, V. Ravyn, L. Wang, A. Ptasznik, and R. G. Collman Signaling Mechanism of HIV-1 gp120 and Virion-Induced IL-1{beta} Release in Primary Human Macrophages J. Immunol., May 15, 2008; 180(10): 6675 - 6684. [Abstract] [Full Text] [PDF]

				A. W. Lee, E. R. Sharp, A. O'Mahony, M. G. Rosenberg, D. M. Israelski, G. P. Nolan, and D. F. Nixon Single-Cell, Phosphoepitope-Specific Analysis Demonstrates Cell Type- and Pathway-Specific Dysregulation of Jak/STAT and MAPK Signaling Associated with In Vivo Human Immunodeficiency Virus Type 1 Infection J. Virol., April 1, 2008; 82(7): 3702 - 3712. [Abstract] [Full Text] [PDF]

				L. Fantuzzi, F. Spadaro, C. Purificato, S. Cecchetti, F. Podo, F. Belardelli, S. Gessani, and C. Ramoni Phosphatidylcholine-specific phospholipase C activation is required for CCR5-dependent, NF-kB-driven CCL2 secretion elicited in response to HIV-1 gp120 in human primary macrophages Blood, April 1, 2008; 111(7): 3355 - 3363. [Abstract] [Full Text] [PDF]

				H. J. Kim, Y. Lee, E.-J. Chang, H.-M. Kim, S.-P. Hong, Z. H. Lee, J. Ryu, and H.-H. Kim Suppression of Osteoclastogenesis by N,N-Dimethyl-D-erythro-sphingosine: A Sphingosine Kinase Inhibition-Independent Action Mol. Pharmacol., August 1, 2007; 72(2): 418 - 428. [Abstract] [Full Text] [PDF]

				B. Majumder, N. J. Venkatachari, E. A. Schafer, M. L. Janket, and V. Ayyavoo Dendritic Cells Infected with vpr-Positive Human Immunodeficiency Virus Type 1 Induce CD8+ T-Cell Apoptosis via Upregulation of Tumor Necrosis Factor Alpha J. Virol., July 15, 2007; 81(14): 7388 - 7399. [Abstract] [Full Text] [PDF]

				Z. Sui, L. F. Sniderhan, G. Schifitto, R. P. Phipps, H. A. Gelbard, S. Dewhurst, and S. B. Maggirwar Functional Synergy between CD40 Ligand and HIV-1 Tat Contributes to Inflammation: Implications in HIV Type 1 Dementia J. Immunol., March 1, 2007; 178(5): 3226 - 3236. [Abstract] [Full Text] [PDF]

				S. M. Wahl, T. Greenwell-Wild, and N. Vazquez HIV accomplices and adversaries in macrophage infection J. Leukoc. Biol., November 1, 2006; 80(5): 973 - 983. [Abstract] [Full Text] [PDF]

				A. David, A. Saez-Cirion, P. Versmisse, O. Malbec, B. Iannascoli, F. Herschke, M. Lucas, F. Barre-Sinoussi, J.-F. Mouscadet, M. Daeron, et al. The Engagement of Activating Fc{gamma}Rs Inhibits Primate Lentivirus Replication in Human Macrophages J. Immunol., November 1, 2006; 177(9): 6291 - 6300. [Abstract] [Full Text] [PDF]

				G. A. Darnell, W. A. Schroder, J. Gardner, D. Harrich, H. Yu, R. L. Medcalf, D. Warrilow, T. M. Antalis, S. Sonza, and A. Suhrbier SerpinB2 Is an Inducible Host Factor Involved in Enhancing HIV-1 Transcription and Replication J. Biol. Chem., October 20, 2006; 281(42): 31348 - 31358. [Abstract] [Full Text] [PDF]

				B. Tomkowicz, C. Lee, V. Ravyn, R. Cheung, A. Ptasznik, and R. G. Collman The Src kinase Lyn is required for CCR5 signaling in response to MIP-1beta and R5 HIV-1 gp120 in human macrophages Blood, August 15, 2006; 108(4): 1145 - 1150. [Abstract] [Full Text] [PDF]

				M. Yadav, L. Clark, and J. S. Schorey Macrophage's Proinflammatory Response to a Mycobacterial Infection Is Dependent on Sphingosine Kinase-Mediated Activation of Phosphatidylinositol Phospholipase C, Protein Kinase C, ERK1/2, and Phosphatidylinositol 3-Kinase J. Immunol., May 1, 2006; 176(9): 5494 - 5503. [Abstract] [Full Text] [PDF]