Disruption of microtubule network in human monocytes induces expression of interleukin-1 but not that of interleukin-6 nor tumor necrosis factor-alpha. Involvement of protein kinase A stimulation.
We have reported recently that colchicine and other microtubule-disrupting agents stimulated interleukin-1 (IL-1) alpha and beta synthesis in human monocytes. In this study we found that unexpectedly colchicine failed to stimulate the expression of two other potent immune mediators, namely tumor necrosis factor-alpha and interleukin-6. Remarkably, taxol which induces stable microtubule bundles, antagonized the colchicine but not the LPS-induced IL-1 synthesis. These results suggested that the colchicine-mediated IL-1 induction was generated by microtubule disassembly. We next demonstrated that microtubule disruption triggered an elevation of intracellular levels of cAMP and a subsequent stimulation of protein kinase A. The use of different protein kinase inhibitors supported a role of the PKA, but not the PKC, in the colchicine-induced IL-1 production. Furthermore, elevation of intracellular cAMP levels by 8-bromo-cAMP, forskolin, or cholera toxin potentiated the effect of suboptimal concentration of colchicine on IL-1 synthesis. However, these agents alone were unable to induce IL-1 synthesis. Therefore, our data indicate that the cAMP/protein kinase A-signaling pathway is necessary but not sufficient to generate IL-1 synthesis by microtubule disruption. Thus, microtubule-disrupting drugs appear as useful tools to further characterize the molecular events which regulate IL-1 production in human monocytes.
Manié
S
S
Institut National de la Santé et de la Recherche Médicale U364, Faculté de Médecine, Nice, France.
Schmid-Alliana
A
A
Kubar
J
J
Ferrua
B
B
Rossi
B
B
D000262:Adenylyl Cyclases / Q000378:metabolism; D002478:Cells, Cultured; D003078:Colchicine / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis*; D008870:Microtubules / Q000187:drug effects / Q000502:physiology*; D009000:Monocytes / Q000378:metabolism* / Q000648:ultrastructure; D017239:Paclitaxel / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D007375:Interleukin-1; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000242:Cyclic AMP; D011494:Protein Kinases; D000262:Adenylyl Cyclases; D017239:Paclitaxel; D003078:Colchicine; D007213:Indomethacin