Podophyllotoxin lignans enhance IL-1beta but suppress TNF-alpha mRNA expression in LPS-treated monocytes.
There exists a growing body of research which indicates that antimitotics such as taxol and colchicine influence cytokine gene expression. In the present study we examined the effect of podophyllotoxin and six analogs on nuclear factor kappa B (NF-kappa B) activation, and on interleukin-1 beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) mRNA expression in human THP-1 monocytes. All compounds were inactive between 0.001microM and 10microM when tested alone. However, podophyllotoxin (0.1 microM) enhanced LPS-induced NF-kappa B activation and IL-1beta mRNA expression between 2 and 3-fold. In contrast, LPS-induced TNF-alpha mRNA expression was decreased between 3 and 6-fold. Comparable results were also observed with the three analogs acetylpodophyllotoxin, 4'-demethylpodophyllotoxin and alpha-peltatin. The remaining three analogs (podophyllotoxin-4-O-glucoside, beta-peltatin-beta-D-glucopyransoide and 1,2,3,4-dehydrodesoxypodophyllotoxin) were inactive. Clearly certain structural features such as the presence of a glycosidic group or ring aromatization results in loss of biological activity. Interestingly, the analogs that were inactive in our assays have also been previously shown to lack affinity for tubulin binding. These results suggest that during the initial hours of exposure to podophyllotoxin or specific analogs these compounds do not act as independent stimulants of human monocyte activation, but can selectively enhance or suppress LPS-induced cytokine gene expression.
Pugh
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Department of Pharmacognosy, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, University 38677, USA.
Khan
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Moraes
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RM
Pasco
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D002478:Cells, Cultured; D004587:Electrophoresis, Agar Gel; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D053583:Interleukin-1beta; D017705:Lignans / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D007375:Interleukin-1; D053583:Interleukin-1beta; D017705:Lignans; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010446:Peptide Fragments; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C056932:interleukin 1beta (193-195); D011034:Podophyllotoxin