The Src kinase Lyn is required for CCR5 signaling in response to MIP-1β and R5 HIV-1 gp120 in human macrophages
| Autor: | Andrzej Ptasznik, Ricky Cheung, Ronald G. Collman, ChuHee Lee, Brian Tomkowicz, Vipa Ravyn |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Chemokine
Receptors CCR5 MAP Kinase Signaling System Mitogen-Activated Protein Kinase 3 viruses Immunology HIV Envelope Protein gp120 Biology Biochemistry LYN Humans Chemokine CCL4 Macrophage inflammatory protein Cells Cultured Chemokines Cytokines and Interleukins Mitogen-Activated Protein Kinase 1 Acquired Immunodeficiency Syndrome Tyrosine-protein kinase CSK Tumor Necrosis Factor-alpha Kinase Macrophages virus diseases Cell Biology Hematology Macrophage Inflammatory Proteins Cell biology src-Family Kinases Chemokines CC HIV-1 biology.protein Tumor necrosis factor alpha Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Blood. 108:1145-1150 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2005-12-012815 |
| Popis: | CCR5 is a receptor for several β chemokines and the entry coreceptor used by macrophage-tropic (R5) strains of HIV-1. In addition to supporting viral entry, CCR5 ligation by the HIV-1 envelope glycoprotein 120 (gp120) can activate intracellular signals in macrophages and trigger inflammatory mediator release. Using a combination of in vitro kinase assay, Western blotting for phospho-specific proteins, pharmacologic inhibition, CCR5 knockout (CCR5Δ32) cells, and kinase-specific blocking peptide, we show for the first time that signaling through CCR5 in primary human macrophages is linked to the Src kinase Lyn. Stimulation of human monocyte-derived macrophages with either HIV-1 gp120 or MIP-1β results in the CCR5-mediated activation of Lyn and the concomitant Lyn-dependent activation of the mitogen-activated protein (MAP) kinase ERK-1/2. Furthermore, activation of the CCR5/Lyn/ERK-1/2 pathway is responsible for gp120-triggered production of TNF-α by macrophages, which is believed to contribute to HIV-1 pathogenesis. Thus, Lyn kinase may play an important role both in normal CCR5 function in macrophages and in AIDS pathogenesis in syndromes such as AIDS dementia where HIV-1 gp120 contributes to inappropriate macrophage activation, mediator production, and secondary injury. |
| Databáze: | OpenAIRE |
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