A novel ERK-dependent signaling process that regulates interleukin-2 expression in a late phase of T cell activation.
Engagement of the T cell antigen receptor (TCR) rapidly induces multiple signal transduction pathways, including ERK activation. Here, we report a critical role for ERK at a late stage of T cell activation. Inhibition of the ERK pathway 2-6 h after the start of TCR stimulation significantly impaired interleukin-2 (IL-2) production, whereas the same treatment during the first 2 h had no effect. ERK inhibition significantly impaired nuclear translocation of c-Rel with a minimum reduction of NF-AT activity. Requirement for sustained ERK activation was also confirmed using primary T cells. To induce sustained activation of ERK, T cells required continuous engagement of TCR. Stimulation of T cells with soluble anti-TCR antibody resulted in activation of ERK lasting for 60 min, but failed to induce IL-2 production. In contrast, plate-bound anti-TCR antibody activated ERK over 4 h and induced IL-2. Furthermore, T cells treated with soluble anti-TCR antibody produced IL-2 when phorbol 12-myristate 13-acetate, which activates ERK, was present in the culture medium 2-6 h after the start of stimulation. Together, the data demonstrate the presence of a novel activation process following TCR stimulation that requires ERK-dependent regulation of c-Rel, a member of the NF-kappaB family.
Koike
Toru
T
Program in Molecular Immunology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, CA 2004, 1120 15th Street, Augusta, GA 30912-2600, USA.
Yamagishi
Hiroko
H
Hatanaka
Yasue
Y
Fukushima
Atsuki
A
Chang
Jing-wen
JW
Xia
Yan
Y
Fields
Mark
M
Chandler
Phillip
P
Iwashima
Makio
M
D021581:Active Transport, Cell Nucleus; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004789:Enzyme Activation; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis*; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D007376:Interleukin-2; D020569:Proto-Oncogene Proteins c-rel; D011948:Receptors, Antigen, T-Cell; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate