Association of decreased phosphorylation of ERK-2 with costimulation of rat T cell activation by MEK-1 inhibitors and TGF-beta 1

Transforming growth factor-beta (TGF-beta) is usually known as an immunosup pressive cytokine, but we and others have shown stimulatory effects of TGF- beta on activation of Th2 T-lymphocytes. In the present investigation we ha ve studied the effect of TGF-beta 1 on phosphorylation of ERK, a MAP-kinase downstream of the Ras pathway. ERK is phosphorylated by MEK-1 and PD098059 and U0126 are specific inhibitors for this kinase. We demonstrate in the p resent study that these inhibitors abrogate the inhibitory effect of adh-sp lc (adherent-spleen cells) on activation of primary rat T-cells and induce a strong costimulatory effect almost as strong as we have previously shown with TGF-beta 1. When TGF-beta 1 is acting stimulatory on T-cell activation , it decreases phosphorylation of ERK-2 and thereby its activation. To inve stigate whether TGF-beta 1 and MEK-1 inhibitors influence the same pathways , we compared their effects on cytokine profiles associated with SEA-induce d rat T cell activation. TGF-beta 1 induced IL-IO production, slightly decr eased TNF-alpha production and decreased IFN-gamma production. The PD098059 inhibitor decreased both IFN-gamma and TNF-alpha production and together w ith TGF-beta 1, it totally blocked IFN- gamma, TNF-alpha and IL-10 producti on. Thus TGF-beta 1 and PD098059 showed overlapping but not identical effec ts on the cytokine pattern. (C) 2000 Published by Elsevier Science B.V. All rights reserved.