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ORIGINAL ARTICLE

Anisodamine Inhibits Shiga Toxin Type 2-Mediated Tumor Necrosis Factor- Production in Vitro and in Vivo¹

Hui-Min Zhang^*, Zhou-Lou Ou and Tatsuo Yamamoto^*,2

^* Department of Bacteriology, Niigata University School of Medicine, Niigata 951–8510, Japan
Department of Clinical Pharmacology, Research Institute, International Medical Center of Japan, Tokyo 162–8655, Japan

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- 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 µg/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- production in a dose- and time-dependent manner. Anisodamine also suppressed Stx2-induced TNF- mRNA expression. Further study showed that endogenous prostaglandin E2 may be involved in this inhibitory effect. In contrast to TNF- mRNA, anisodamine at concentrations as high as 400 µg/ml did not decrease Stx2-induced IL-1ß and IL-8 mRNA levels. In addition, anisodamine (>50 µg/ml) increased Stx2-stimulated THP-1 cell viability. Levels of TNF- 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- 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.

Key Words: anisodamine • Stx2 • TNF-

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