Exogenous Nef is an inhibitor of Mycobacterium tuberculosis-induced tumor necrosis factor-alpha production and macrophage apoptosis.

Abstract

Human immunodeficiency virus-1 (HIV-1) impairs tumor necrosis factor-alpha (TNF-alpha)-mediated macrophage apoptosis induced by Mycobacterium tuberculosis (Mtb). HIV Nef protein plays an important role in the pathogenesis of AIDS. We have tested the hypothesis that exogenous Nef is a factor that inhibits TNF-alpha production/apoptosis in macrophages infected with Mtb. We demonstrate that Mtb and Nef individually trigger TNF-alpha production in macrophages. However, TNF-alpha production is dampened when the two are present simultaneously, probably through cross-regulation of the individual signaling pathways leading to activation of the TNF-alpha promoter. Mtb-induced TNF-alpha production is abrogated upon mutation of the Ets, Egr, Sp1, CRE, or AP1 binding sites on the TNF-alpha promoter, whereas Nef-mediated promoter activation depends only on the CRE and AP1 binding sites, pointing to differences in the mechanisms of activation of the promoter. Mtb-dependent promoter activation depends on the mitogen-activated kinase (MAPK) kinase kinase ASK1 and on MEK/ERK signaling. Nef inhibits ASK1/p38 MAPK-dependent Mtb-induced TNF-alpha production probably by inhibiting binding of ATF2 to the TNF-alpha promoter. It also inhibits MEK/ERK-dependent Mtb-induced binding of FosB to the promoter. Nef-driven TNF-alpha production occurs in an ASK1-independent, Rac1/PAK1/p38 MAPK-dependent, and MEK/ERK-independent manner. The signaling pathways used by Mtb and Nef to trigger TNF-alpha production are therefore distinctly different. In addition to attenuating Mtb-dependent TNF-alpha promoter activation, Nef also reduces Mtb-dependent TNF-alpha mRNA stability probably through its ability to inhibit ASK1/p38 MAPK signaling. These results provide new insight into how HIV Nef probably exacerbates tuberculosis infection by virtue of its ability to dampen Mtb-induced TNF-alpha production.

• Authors: Kuldeep Kumawat, Sushil Kumar Pathak, Anna-Lena Spetz, Manikuntala Kundu, Joyoti Basu
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 17 Pg. 12629-37 (Apr 23 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20068037 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATF2 protein, human
• Activating Transcription Factor 2
• FOSB protein, human
• Proto-Oncogene Proteins c-fos
• RAC1 protein, human
• RNA, Messenger
• Tumor Necrosis Factor-alpha
• nef Gene Products, Human Immunodeficiency Virus
• nef protein, Human immunodeficiency virus 1
• PAK1 protein, human
• p21-Activated Kinases
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase Kinase 5
• MAP3K5 protein, human
• rac1 GTP-Binding Protein

Topics

• Acquired Immunodeficiency Syndrome (metabolism, microbiology)
• Activating Transcription Factor 2 (metabolism)
• Apoptosis
• Cell Line
• HIV-1 (metabolism, pathogenicity)
• Humans
• MAP Kinase Kinase Kinase 5 (metabolism)
• MAP Kinase Signaling System (drug effects)
• Macrophages (metabolism, microbiology, virology)
• Mycobacterium tuberculosis (metabolism)
• Proto-Oncogene Proteins c-fos (metabolism)
• RNA Stability (drug effects)
• RNA, Messenger (metabolism)
• Response Elements
• Tuberculosis (metabolism, virology)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, biosynthesis)
• nef Gene Products, Human Immunodeficiency Virus (metabolism, pharmacology)
• p21-Activated Kinases (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)
• rac1 GTP-Binding Protein (metabolism)