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Department of Immunology, Merck Research Laboratories, Rahway, NJ 07065
Productive T cell activation leading to cytokine secretion requires
the cooperation of multiple signaling pathways coupled to the TCR and
to costimulatory molecules such as CD28. Here, we utilized two
pharmacophores, PD98059 and FK506, that inhibit, respectively,
mitogen-activated protein (MAP) kinase kinase 1 (MEK 1) and
calcineurin, to determine the relative role of the signaling pathways
controlled by these enzymes in T cell activation. Although the two
compounds had distinctive effects on CD69 induction, they both
suppressed T cell proliferation induced by anti-CD3 mAb, in a
manner reversible by exogenous IL-2, suggesting that PD98059, like
FK506, affects the production of, rather than the responsiveness to
growth-promoting cytokines. Accordingly, IL-2 production by T cells
stimulated with anti-CD3 mAb in conjunction with PMA or with
anti-CD28 mAb was inhibited by both compounds. However, these
compounds differentially affected the production of other cytokines,
depending on the mode of activation. PD98059 inhibited TNF-
, IL-3,
granulocyte-macrophage (GM)-CSF, IFN-
, and to a lesser extent IL-6
and IL-10 production but enhanced IL-4, IL-5, and IL-13 production
induced by CD3/PMA or CD3/CD28. FK506 suppressed CD3/PMA-induced
production of all cytokines examined here but to a lesser extent IL-13.
FK506 also reduced CD3/CD28-induced production of IL-3, IL-4, IL-10,
TNF-, and IL-6 but augmented that of GM-CSF, IL-5, IFN-, and
IL-13. Therefore, the biochemical targets of PD98059 and FK506
contribute differently to the production of various cytokines by T
cells, which may have implications for the therapeutic manipulation of
this production.
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