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Justicidin A Inhibits the Transport of Tumor Necrosis Factor- to Cell Surface in Lipopolysaccharide-Stimulated RAW 264.7 Macrophages

Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan (L.-T.T., J.-P.W.); and School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan (C.-N.L.)

Exposure of macrophages to lipopolysaccharide (LPS) induces release of tumor necrosis factor- (TNF-), which is initially synthesized as a 26-kDa pro-TNF- followed by proteolytic processing to a 17-kDa secreted form. In this study, justicidin A, an arylnaphthalide lignan isolated from Justicia procumbens, was found to inhibit LPS-stimulated TNF- release from RAW 264.7 macrophages in a concentration- and time-dependent manner, and the underlying mechanism was investigated. In the presence of justicidin A, challenge with LPS increased the steady-state level of the 26-kDa membrane-bound form of TNF- protein, whereas justicidin A had little effect on the expression of TNF- mRNA and on the synthesis of pro-TNF- protein. Results of the pulse-chase experiment, revealed that the conversion of pro-TNF- to mature TNF- was inhibited by justicidin A. Moreover, justicidin A suppressed the transport of TNF- to cell surface as analyzed by flow cytometry. The immunofluorescence analysis demonstrated that large amounts of LPS-induced TNF- accumulated primarily within Golgi complex. These results indicate that justicidin A inhibits TNF- release at the step of transport of pro-TNF- to cell surface, and this leads to the accumulation of TNF- in Golgi complex in RAW 264.7 macrophages.

Address correspondence to: Jih-Pyang Wang, Department of Education and Research, Taichung Veterans General Hospital, 160, Chung-Kang Road, Sec. 3, Taichung, Taiwan 407, Republic of China. E-mail: w1994{at}vghtc.gov.tw

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