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.
It has been shown that stimulation of lymphoid cells causes the activation of the extracellular signal-regulated-2 (ERK-2) which activates nuclear factor of activated T cells (NF-AT), a transcription factor involved in the regulation of interleukin-2 (1L2) gene transcription. ERK-2 is activated via a kinase cascade initiated by activation of the G protein p21Ras followed by phosphorylation and activation of Raf-1 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 shown that a blockade of this cascade did not perturb lymphocyte stimulation and proliferation. In the present paper, we studied in human primary T cells the possible involvement of the Raf-1/MEK-1/ERK-2 pathway upon stimulation by jacalin, a mitogenic lectin which specifically stimulates CD4+ lymphocytes. We show here that the mitogen-activated protein (MAP) kinase pathway was stimulated in human purified lymphocytes upon activation with jacalin. Moreover, activation of this pathway appeared 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 cell mitogenic lectin, blockade of MEK-1 reduced but did not totally inhibit either ERK-2 phosphorylation or IL2 mRNA expression. This shows, as already suggested, that another pathway in addition to the Raf-1/MEK-1/ERK-2 kinase cascade could be triggered in T cell activation. Jacalin 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 the characterisation of drugs specifically targeted to this particular pathway.
Lafont
V
V
INSERM U431, Microbiologie et Pathologie Cellulaire Infectieuse, Université de Montpellier II, France.
Rouot
B
B
Favero
J
J
D005786:Gene Expression Regulation; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D007700:Kinetics; D037102:Lectins / Q000494:pharmacology*; D008213:Lymphocyte Activation; D010766:Phosphorylation; D037121:Plant Lectins; D011494:Protein Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D014158:Transcription, Genetic
D007376:Interleukin-2; D037102:Lectins; D037121:Plant Lectins; D012333:RNA, Messenger; C043696:jacalin; D011494:Protein Kinases