Zinc ions suppress mitogen-activated interleukin-2 production in Jurkat cells.
Calcineurin (CN) is thought to play an important role in the immune system by regulating cytokine production, for example, interleukin-2 (IL-2) in T-lymphocytes. We have previously shown that physiological concentrations of Zn2+ inhibit CN activity in vitro [K. Takahashi, E. Akaishi, Y. Abe, R. Ishikawa, S. Tanaka, K. Hosaka, Y. Kubohara, Zinc inhibits calcineurin activity in vitro by competing with nickel, Biochem. Biophys. Res. Commun. 307 (2003) 64-68], in spite of the fact that Zn2+ is an essential element of the CN catalytic domain. In this study, in order to assess whether Zn2+ regulates (suppresses) CN activity in vivo and whether Zn2+ can be used as an anti-inflammatory and/or immunosuppressive drug, we examined the effects of Zn2+ on IL-2 production induced by the mitogen, concanavalin A (ConA), in Jurkat T-cells. Zn2+ at 0.2 mM suppressed ConA-induced IL-2 accumulation in the medium of an in vitro culture of Jurkat cells. Zn2+ at 0.03-0.3 mM dose-dependently suppressed ConA-induced IL-2 mRNA expression in Jurkat cells. Zn2+ also suppressed IL-2 mRNA expression induced by phorbol ester (PMA) and ionomycin. Furthermore, Zn2+ and the immunosuppressant FK506 showed an additive inhibitory effect on ConA-induced IL-2 mRNA expression. These results suggest that exogenously added Zn2+ may disturb (increase) the intracellular Zn2+ concentration and inhibit CN activity, thereby suppressing IL-2 production in Jurkat cells. The present study further indicates that Zn2+ may have therapeutic potential in the treatment of T-cell related inflammation and also that Zn2+ may be utilized as a supplemental drug with FK506.
Tanaka
Susumu
S
Department of Health and Nutrition, Faculty of Health and Welfare, Takasaki University of Health and Welfare, Takasaki 370-0033, Japan.
Akaishi
Emi
E
Hosaka
Kohei
K
Okamura
Shinichi
S
Kubohara
Yuzuru
Y
D002413:Cations, Divalent / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D015759:Ionomycin / Q000494:pharmacology; D019169:Jurkat Cells; D008934:Mitogens / Q000494:pharmacology*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016559:Tacrolimus / Q000494:pharmacology; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology*
D002413:Cations, Divalent; D007376:Interleukin-2; D008934:Mitogens; D012333:RNA, Messenger; D003208:Concanavalin A; D015240:Phorbol 12,13-Dibutyrate; D015759:Ionomycin; D015032:Zinc; D016559:Tacrolimus