p38 MAP kinase and MKK-1 co-operate in the generation of GM-CSF from LPS-stimulated human monocytes by an NF-κB-independent mechanism
| Autor: | Meja, Koremu K, Seldon, Paul M, Nasuhara, Yasuyuki, Ito, Kazuhiro, Barnes, Peter J, Lindsay, Mark A, Giembycz, Mark A |
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| Jazyk: | angličtina |
| Rok vydání: | 2000 |
| Předmět: |
Flavonoids
Lipopolysaccharides Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinase 3 Pyridines Tumor Necrosis Factor-alpha Imidazoles MAP Kinase Kinase 1 NF-kappa B Granulocyte-Macrophage Colony-Stimulating Factor Protein Serine-Threonine Kinases p38 Mitogen-Activated Protein Kinases Monocytes Papers Humans RNA Messenger Enzyme Inhibitors Mitogen-Activated Protein Kinases |
| Popis: | 1. The extent to which the p38 mitogen-activated protein (MAP) kinase and MAP kinase kinase (MKK)-1-signalling pathways regulate the expression of granulocyte/macrophage colony-stimulating factor (GM-CSF) from LPS-stimulated human monocytes has been investigated and compared to the well studied cytokine tumour necrosis factor-alpha (TNF alpha). 2. Lipopolysaccharide (LPS) evoked a concentration-dependent generation of GM-CSF from human monocytes. Temporally, this effect was preceded by an increase in GM-CSF mRNA transcripts and abolished by actinomycin D and cycloheximide. 3. LPS-induced GM-CSF release and mRNA expression were associated with a rapid and time-dependent activation of p38 MAP kinase, ERK-1 and ERK-2. 4. The respective MKK-1 and p38 MAP kinase inhibitors, PD 098059 and SB 203580, maximally suppressed LPS-induced GM-CSF generation by90%, indicating that both of these signalling cascades co-operate in the generation of this cytokine. 5. Electrophoretic mobility shift assays demonstrated that LPS increased nuclear factor kappa B (NF-kappa B) : DNA binding. SN50, an inhibitor of NF-kappa B translocation, abolished LPS-induced NF-kappaB : DNA binding and the elaboration of TNFalpha, a cytokine known to be regulated by NF-kappaB in monocytes. In contrast, SN50 failed to affect the release of GM-CSF from the same monocyte cultures. 6. Collectively, these results suggest that the generation of GM-CSF by LPS-stimulated human monocytes is regulated in a co-operative fashion by p38 MAP kinase- and MKK-1-dependent signalling pathways independently of the activation of NF-kappa B. |
| Databáze: | OpenAIRE |
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