Manganese promotes phorbol ester-induced interleukin-2 production via AP-1 activation in Jurkat T-cells.

Mn2+ is a minor nutrient, but is essential for numerous enzymatic activities and thus, for many cellular functions. However, its physiological roles and toxicity remain to be elucidated. In this study, we assessed the pharmacological potential and toxicity of Mn2+ in the immune system by examining the effects of Mn2+ on interleukin-2 (IL-2) production by Jurkat T-cells. Mn2+ at 0.1-1 mM did not significantly induce IL-2 production, whereas phorbol 12-myristate 13-acetate (PMA) at 1 mu M slightly induced IL-2 production. Interestingly, Mn2+ at 0.3-0.7 mM promoted PMA-induced IL-2 production in a dose-dependent manner. A reporter gene assay revealed that Mn2+ promoted the activity of AP-1 (activator protein-1, a complex of c-Fos and c-Jun) in the presence of PMA. Western blot analysis showed that Mn2+ promoted the activation of JNK2 (c-Jun N-terminal kinase 2) and p38 MAPK (mitogen-activated protein kinase), which are both activators of AP-1, and upregulated the production of c-Fos and c-Jun within 4 h in the presence of PMA. These results suggest that Mn2+ promotes PMA-induced IL-2 production by inducing the production and activation of AP-1, at least in part. (c) 2012 Elsevier Ireland Ltd. All rights reserved.