THE RAF-1 MITOGEN-ACTIVATED PROTEIN-KINASE KINASE-1 EXTRACELLULAR SIGNAL-REGULATED-2 SIGNALING PATHWAY AS PREREQUISITE FOR INTERLEUKIN-2 GENE-TRANSCRIPTION IN LECTIN-STIMULATED HUMAN PRIMARY T-LYMPHOCYTES
V. Lafont et al., THE RAF-1 MITOGEN-ACTIVATED PROTEIN-KINASE KINASE-1 EXTRACELLULAR SIGNAL-REGULATED-2 SIGNALING PATHWAY AS PREREQUISITE FOR INTERLEUKIN-2 GENE-TRANSCRIPTION IN LECTIN-STIMULATED HUMAN PRIMARY T-LYMPHOCYTES, Biochemical pharmacology, 55(3), 1998, pp. 319-324
It has been shown that stimulation of lymphoid cells causes the activa
tion oi the extracellular signal regulated-2 (ERK-2) which activates n
uclear factor oi activated T cells (NF-AT), a transcription factor inv
olved in the regulation of interleukin-2 (IL2) gene transcription. ERK
-2 is activated via a kinase cascade initiated by activation of the G
protein p21Ras followed by phosphorylation and activation oi Rai-l and
mitogen activated protein kinase kinase-1 (MEK-1). Activation of this
pathway has been described primarily in human T cell lines; however,
using primary T lymphocytes from transgenic mice, a recent study has s
hown that a blockade oi this cascade did not perturb lymphocyte stimul
ation and proliferation. In the present paper, we studied in human pri
mary T cells the possible involvement of the Raf-1/MEK-1/ERK-2 pathway
upon stimulation by jacalin, a mitogenic lectin which specifically st
imulates CD4(+) lymphocytes. We show here that the mitogen-activated p
rotein (MAP) kinase pathway was stimulated in human purified lymphocyt
es upon activation with jacalin. Moreover, activation oi this pathway
appeal-ed to be essential, since its blockade by a specific inhibitor
of the MEK-1 kinase abolished IL2 gene transcription; in contrast, in
T cells stimulated with phytohemagglutinin M(PHA), another potent T ce
ll mitogenic lectin, blockade oi MEK-1 reduced but did not totally inh
ibit either ERK-2 phosphorylation or IL2 mRNA expression. This shows,
as already suggested, that another pathway in addition to the Raf-1/ME
K-1/ERK-2 kinase cascade could be triggered in T cell activation. Jaca
lin stimulation therefore appeared to be a good model for the specific
activation of the MAP kinase pathway in human primary T lymphocytes,
which would allow die characterisation of drugs specifically targeted
to this particular pathway. (C) 1998 Elsevier Science Inc.