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Mitogen-Activated Protein Kinase Is Activated by CD28-Mediated Signaling and Is Required for IL-4 Production by Human CD4+CD45RO+ T Cells and Th2 Effector Cells1
R. W. Johnson Pharmaceutical Research Institute, Drug Discovery Research, Raritan, NJ 08869
T cell proliferation and cytokine production usually require
stimulation via both the TCR/CD3 complex and the CD28 costimulatory
receptor. Using purified human CD4+ peripheral blood T
cells, we show that CD28 stimulation alone activates p38
mitogen-activated protein kinase (p38). Cell proliferation induced
by CD28 stimulation alone, a response attributed to
CD4+CD45RO+ memory T cells, was blocked by the
highly specific p38 inhibitors SB 203580 (IC50 =
10–80 nM) and RWJ 67657 (IC50 = 0.5–4 nM). In
contrast, proliferation induced by anti-CD3 plus anti-CD28 mAbs
was not blocked. Inhibitors of p38 also blocked CD4+ T cell
production of IL-4 (SB 203580 IC50 = 20–100 nM), but
not IL-2, in response to CD3 and CD28 stimulation. IL-5, TNF-, and
IFN-
production were also inhibited, but to a lesser degree than
IL-4. IL-4 production was attributed to
CD4+CD45RO+ T cells, and its induction was
suppressed by p38 inhibitors at the mRNA level. In polarized Th1 and
Th2 cell lines, SB 203580 strongly inhibited IL-4 production by Th2
cells (IC50 = 10–80 nM), but only partially inhibited
IFN- and IL-2 production by Th1 cells (<50% inhibition at 1 µM).
In both Th1 and Th2 cells, CD28 signaling activated p38 and was
required for cytokine production. These results show that p38 plays
an important role in some, but not all, CD28-dependent cellular
responses. Its preferential involvement in IL-4 production by
CD4+CD45RO+ T cells and Th2 effector cells
suggests that p38 may be important in the generation of Th2-type
responses in humans.
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