Hypothemycin inhibits the proliferative response and modulates the production of cytokines during T cell activation

Hypothemycin, a resorcylic acid lactone antibiotic, was identified as activ e in a screen for inhibitors of T cell activation. It was found to inhibit the proliferation of mouse and human T cells stimulated with anti-CD3 mAb PMA and of human PBMC stimulated with anti-CD3 mAb alone. This inhibition was partially reversed by exogenous IL-2 indicating that it is not due to n on-specific toxicity. Hypothemycin potently suppressed the production of IL -2 (IC50: 9 nM) but affected IL-2-induced proliferation to a lesser extent (IC50: 194 nM). Hypothemycin also inhibited IL-6, IL-10, IFN-gamma and TNF- alpha production. By contrast, it markedly enhanced the production of IL-4, IL-5 and IL-13. These effects were seen both at the mRNA and protein secre tion levels. Analysis of the effect of hypothemycin on CD69 induction sugge sted that it disrupts calcineurin-independent rather than calcineurin-depen dent signaling. Furthermore, hypothemycin was able to inhibit the phosphory lation of ERK1/2 induced by PMA treatment of T cells. Therefore, hypothemyc in represents an inhibitor of T cell activation with a novel mode of action and unique modulatory activity on cytokine production. (C) 1999 Elsevier S cience B.V. All rights reserved.