INHIBITION OF MITOGEN-ACTIVATED PROTEIN-KINASE KINASE BLOCKS T-CELL PROLIFERATION BUT DOES NOT INDUCE OR PREVENT ANERGY

Three mitogen-activated protein kinase pathways are up-regulated durin g the activation of T lymphocytes, the extracellular signal-regulated kinase (ERK), Jun NH2-terminal kinase, and p38 mitogen-activated prote in kinase pathways. To examine the effects of blocking the ERK pathway on T cell activation, we used the inhibitor U0126, which has been sho wn to specifically block mitogen-activated protein kinase/ERK kinase ( MEK), the kinase upstream of ERK, This compound inhibited T cell proli feration in response to antigenic stimulation or cross-linked anti-CDS plus anti-CD28 Abs, but had no effect on IL-2-induced proliferation. The block in T cell proliferation was mediated by down-regulating IL-2 mRNA-levels. Blocking Ag-induced proliferation by inhibiting MEK did not induce anergy, unlike treatments that block entry into the cell cy cle following antigenic stimulation. Surprisingly, induction of anergy in T cells exposed to TCR cross-linking in the absence of costimulati on was also not affected by blocking MEK, unlike cyclosporin A treatme nt that blocks anergy induction. These results suggest that inhibition of MEK prevents T cell proliferation in the short term, but does not cause any long-term effects on either T cell activation or induction o f anergy. These findings may help determine the viability of using mit ogen-activated protein kinase inhibitors as immune suppressants.