title: Anisodamine inhibits shiga toxin type 2-mediated tumor necrosis factor-alpha production in vitro and in vivo.
abstract: Cytokines, in particular tumor necrosis factor (TNF), appear to be necessary to develop the pathological process of Shiga toxin-producing Escherichia coli (STEC) infection. In this study we examined the effect of anisodamine, a vasoactive drug, on TNF-alpha production in Shiga toxin type 2 (Stx2)-stimulated human monocytic cells in vitro and in Stx2-injected mice sera in vivo. Human monocytes and THP-1 cells were stimulated by Stx2 (1-100 ng/ml) with or without anisodamine addition (1-400 micrograms/ml). For in vivo evaluations, C57BL/6 mice were given a single intraperitoneal injection of anisodamine (6-50 mg/kg) or saline after intraperitoneal injection of Stx2 (50 ng/kg). The results showed that anisodamine suppressed Stx2-induced TNF-alpha production in a dose- and time-dependent manner. Anisodamine also suppressed Stx2-induced TNF-alpha mRNA expression. Further study showed that endogenous prostaglandin E2 may be involved in this inhibitory effect. In contrast to TNF-alpha mRNA, anisodamine at concentrations as high as 400 micrograms/ml did not decrease Stx2-induced IL-1 beta and IL-8 mRNA levels. In addition, anisodamine (> 50 micrograms/ml) increased Stx2-stimulated THP-1 cell viability. Levels of TNF-alpha in anisodamine-treated mice sera were significantly lower than those in the saline-treated group 1.5 and 24 hr after Stx2 injection. Anisodamine induced a lower percentage of death in Stx2-injected mice. Taken together, our results indicate that anisodamine has an important regulatory effect on Stx2-induced TNF-alpha production in vitro and in vivo. The present study suggested that this drug should be further investigated for its effects on Stx2-mediated diseases in humans.
authors.affiliation: Department of Bacteriology, Niigata University School of Medicine, Niigata 951-8510, Japan.
authors.forename: H M
authors.initials: HM
authors.lastname: Zhang
authors.forename: Z L
authors.initials: ZL
authors.lastname: Ou
authors.forename: T
authors.initials: T
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology; D022641:Shiga Toxin 2 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000494:pharmacology; D012991:Solanaceous Alkaloids / Q000378:metabolism / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004365:Drugs, Chinese Herbal; D007375:Interleukin-1; D016209:Interleukin-8; D022641:Shiga Toxin 2; D012991:Solanaceous Alkaloids; D014409:Tumor Necrosis Factor-alpha; C003922:anisodamine; D016753:Interleukin-10; D015232:Dinoprostone