N. Coudronniere et al., NF-kappa B activation induced by T cell receptor/CD28 costimulation is mediated by protein kinase C-theta, P NAS US, 97(7), 2000, pp. 3394-3399
Citations number
51
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Protein kinase C-theta (PKC theta) is a Ca2+-independent member of the PKC
family that is selectively expressed in skeletal muscle and T lymphocytes a
nd plays an important role in T cell activation. However, the molecular bas
is for the important functions of PKC theta in T cells and the manner in wh
ich it becomes coupled to the T cell receptor-signaling machinery are unkno
wn. We addressed the functional relationship between PKC theta and CD28 cos
timulation, which plays an essential role in T cell receptor-mediated IL-2
production. Here, we provide evidence that PKC theta is functionally couple
d to CD28 costimulation by virtue of its selective ability to activate the
CD28RE/activator protein-1 (AP-1) element in the IL-2 gene promoter. First,
CD28 costimulation enhanced the membrane translocation and catalytic activ
ation of PKC theta. Second, among several PKC isoforms, PKC theta was the o
nly one capable of activating NF-kappa B or CD28RE/AP-1 reporters in T cell
s (but not in 293T cells). Third, wild-type PKC theta synergized with CD28/
CD3 signals to activate CD28RE/AP-1. In addition, PKC theta selectively syn
ergized with Tat to activate a CD28RE/AP-1 reporter. Fourth, CD3/CD28-induc
ed CD28RE/AP-1 activation and NF-kappa B nuclear translocation were blocked
by a selective PKC theta inhibitor. Last PKC theta-mediated activation of
the same reporter was inhibited by the proteasome inhibitor MG132 (which bl
ocks I kappa B degradation) and was found to involve I kappa B-kinase beta.
These findings identify a unique PKC theta-mediated pathway for the costim
ulatory action of CD28, which involves activation of the I kappa B-kinase b
eta/I kappa B/NF-kappa B-signaling cascade.