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 during the activation of T lymphocytes, the extracellular signal-regulated kinase (ERK), Jun NH2-terminal kinase, and p38 mitogen-activated protein kinase pathways. To examine the effects of blocking the ERK pathway on T cell activation, we used the inhibitor U0126, which has been shown to specifically block mitogen-activated protein kinase/ERK kinase (MEK), the kinase upstream of ERK. This compound inhibited T cell proliferation in response to antigenic stimulation or cross-linked anti-CD3 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 cycle following antigenic stimulation. Surprisingly, induction of anergy in T cells exposed to TCR cross-linking in the absence of costimulation was also not affected by blocking MEK, unlike cyclosporin A treatment 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 of anergy. These findings may help determine the viability of using mitogen-activated protein kinase inhibitors as immune suppressants.
DeSilva
D R
DR
Inflammatory Diseases Research, DuPont Merck Pharmaceutical Company, Wilmington, DE 19880, USA.
Jones
E A
EA
Favata
M F
MF
Jaffee
B D
BD
Magolda
R L
RL
Trzaskos
J M
JM
Scherle
P A
PA
D000818:Animals; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002999:Clone Cells; D007376:Interleukin-2 / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D020929:Mitogen-Activated Protein Kinase Kinases; D011494:Protein Kinases / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D018106:CD28 Antigens; D017252:CD3 Complex; D007376:Interleukin-2; D011494:Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases