Colchicine down-regulates lipopolysaccharide-induced granulocyte-macrophage colony-stimulating factor production in murine macrophages
| Autor: | P, Rao, L A, Falk, S F, Dougherty, T, Sawada, D H, Pluznik |
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| Rok vydání: | 1997 |
| Předmět: |
Cell Nucleus
Lipopolysaccharides Time Factors Paclitaxel Transcription Genetic Macrophages NF-kappa B Down-Regulation Granulocyte-Macrophage Colony-Stimulating Factor Biological Transport Microtubules Cell Line Mice Gene Expression Regulation Tubulin Calcium-Calmodulin-Dependent Protein Kinases Animals Tyrosine RNA Messenger Phosphorylation Colchicine Promoter Regions Genetic |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 159(7) |
| ISSN: | 0022-1767 |
| Popis: | Activation of macrophages by LPS and taxol results in production of IL-1, IL-6, TNF-alpha, and granulocyte-macrophage CSF (GM-CSF), which are involved in regulating hemopoiesis, inflammation, and immune responses. Microtubules are proposed as a target site for LPS interaction(s), based on similarities between the effects of the tubulin-binding drug taxol and LPS. To clarify the role of microtubules in LPS-induced GM-CSF expression in macrophages, we examined whether microtubule depolymerizing agents affect GM-CSF production in macrophages. Pretreatment with colchicine impaired LPS induction of GM-CSF in RAW 264 cells, and studies using stable transfectants revealed that colchicine impaired the transcriptional responsiveness of a reporter gene driven by a GM-CSF promoter sequence. Colchicine inhibition of the GM-CSF response correlated with decreases in the mRNA levels of beta-tubulin; maximal inhibition of both events was observed 4 h after addition of colchicine. Microtubule agents inhibited LPS induction of IL-6 and TNF-alpha, while the induction of both IL-1beta and inducible nitric oxide synthase was unaltered, suggesting that LPS activates microtubule-dependent and -independent pathways. Interestingly, LPS stimulation of macrophages down-regulated levels of beta-tubulin transcripts, implying that LPS interacts with an element(s) of the microtubule network in vivo, activating pathways regulating transcription of beta-tubulin. The ability of both colchicine and LPS to modulate transcription of beta-tubulin suggests that this event does not per se underlie the inhibitory effect of colchicine on LPS-induced GM-CSF expression. These data led us to conclude that colchicine inhibits LPS induction of GM-CSF by affecting microtubule-dependent costimulatory signaling pathways that synergize with primary LPS-triggered responses. |
| Databáze: | OpenAIRE |
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