Taxol enhances but does not induce interleukin-1 beta and tumor necrosis factor-alpha production.
Taxol is a potent, microtubule-stabilizing, antineoplastic drug that induces interleukin-1-beta (IL-1-beta) and tumor necrosis factor-alpha (TNF-alpha) release by thioglycolate-elicited mouse peritoneal macrophages. Because taxol use and subsequent cytokine release in human subjects could be associated with toxicity, the present study was performed to determine how taxol affects cytokine production from fresh human mononuclear cells. Cells were incubated overnight with varying doses of bacterial endotoxin, either with or without taxol, 10 mumol/L. Taxol alone did not induce IL-1-beta or TNF-alpha release by mononuclear cells. However, at all doses of endotoxin from 1 pg/ml to 1 microgram/ml, the addition of taxol resulted in a 50% to 100% increase in IL-1-beta release (p < 0.001) and a 25% to 50% increase in TNF-alpha release (p < 0.01). In contrast, taxol caused a reduction in intracellular pro-IL-1-beta levels. Kinetic studies demonstrated that taxol enhanced IL-1-beta release by mononuclear cells at all time points tested from 4.5 hours to 18 hours after stimulation. Taxol alone did not stimulate IL-1-beta or TNF-alpha mRNA transcription. A similar enhancement of IL-1-beta release was noted in endotoxin-stimulated alveolar macrophages. In summary, these results show that under endotoxin-free conditions, the microtubule-stabilizing agent taxol does not induce IL-1-beta or TNF-alpha production by human mononuclear cells or alveolar macrophages but does enhance production of both of these cytokines in conjunction with a second stimulus.
Allen
J N
JN
Moore
S A
SA
Wewers
M D
MD
D015152:Blotting, Northern; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000494:pharmacology; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017239:Paclitaxel / Q000494:pharmacology*; D011498:Protein Precursors / Q000096:biosynthesis; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D007375:Interleukin-1; D008070:Lipopolysaccharides; D011498:Protein Precursors; D014409:Tumor Necrosis Factor-alpha; C043830:interleukin 1 precursor; D015847:Interleukin-4; D017239:Paclitaxel