HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation Journal Article
| Authors: | Muthumani, K.; Choo, A. Y.; Hwang, D. S.; Premkumar, A.; Dayes, N. S.; Harris, C.; Green, D. R.; Wadsworth, S. A.; Siekierka, J. J.; Weiner, D. B. |
| Article Title: | HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation |
| Abstract: | The human immunodeficiency virus (HIV) has been reported to target noninfected CD4 and CD8 cells for destruction. This effect is manifested in part through up-regulation of the death receptor Fas ligand (FasL) by HIV-1 negative factor (Nef), leading to bystander damage. However, the signal transduction and transcriptional regulation of this process remains elusive. Here, we provide evidence that p38 mitogen-activated protein kinase (MAPK) is required for this process. Loss-of-function experiments through dominant-negative p38 isoform, p38 siRNA, and chemical inhibitors of p38 activation suggest that p38 is necessary for Nef-induced activator protein-1 (AP-1) activation, as inhibition leads to an attenuation of AP-1-dependent transcription. Furthermore, mutagenesis of the FasL promoter reveals that its AP-1 enhancer element is required for Nef-mediated transcriptional activation. Therefore, a linear pathway for Nef-induced FasL expression that encompasses p38 and AP-1 has been elucidated. Furthermore, chemical inhibition of the p38 pathway attenuates HIV-1-mediated bystander killing of CD8 cells in vitro. |
| Keywords: | apoptosis; infection; phosphorylation; macrophages; in-vitro; cells; protein-kinase; cytotoxic t-lymphocytes; signaling events; ligand expression |
| Journal Title: | Blood |
| Volume: | 106 |
| Issue: | 6 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2005-09-15 |
| Start Page: | 2059 |
| End Page: | 2068 |
| Language: | English |
| DOI: | 10.1182/blood-2005-03-0932 |
| ACCESSION: | WOS:000231817400034 |
| PROVIDER: | wos |
| PMCID: | PMC1895138 |
| PUBMED: | 15928037 |
| Notes: | --- - Article - "Source: Wos" |
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