Podophyllotoxin lignans enhance IL-1 beta but suppress TNF-alpha mRNA expression in LPS-treated monocytes

There exists a growing body of research which indicates that antimitotics s uch as taxol and colchicine influence cytokine gene expression. In the pres ent study we examined the effect of podophyllotoxin and six analogs on nucl ear factor kappa B (NF-kappa B) activation, and on interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) mRNA expression in human THP-1 monocytes. All compounds were inactive between 0.01 muM and 10 muM w hen tested alone. However, podophyllotoxin (0.1 muM) enhanced LPS-induced N F-kappa B activation and IL-IP mRNA expression between 2 and 3-fold. In con trast, LPS-induced TNF-alpha mRNA expression was decreased between 3 and 6- fold. Comparable results were also observed with the three analogs acetylpo dophyllotoxin, 4 ' -demethylpodophyllotoxin and alpha -peltatin. The remain ing three analogs (podophyllotoxin-4-O-gtucoside, beta -peltatin-beta -D-gl ucopyransoide and 1,2,3,4-dehydrodesoxypodophyllotoxin) were inactive. Clea rly 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 sh own 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 activatio n, but can selectively enhance or suppress LPS-induced cytokine gene expres sion.