Protein kinase C-theta participates in NF-kappa B activation induced by CD3-CD28 costimulation through selective activation of I kappa B kinase beta

The NF-kappa B/Rel family of eukaryotic transcription factors plays an esse ntial role in the regulation of inflammatory, antiapoptotic, and immune res ponses. NF-kappa B is activated by many stimuli including costimulation of T cells with ligands specific for the T-cell receptor (TCR)-CD3 complex and CD28 receptors. However, the signaling intermediates that transduce these costimulatory signals from the TCR-CD3 and CD28 surface receptors leading t o nuclear NF-kappa B expression are not well defined. We now show that prot ein kinase C-theta (PKC-theta), a novel PKC isoform, plays a central role i n a signaling pathway induced by CD3-CD28 costimulation leading to activati on of NF-kappa B in Jurkat T cells. We find that expression of a constituti vely active mutant of PKC-theta potently induces NK-kappa B activation and stimulates the RE/AP composite enhancer from the interleukin-2 gene. Conver sely, expression of a kinase-deficient mutant or antisense PKC-theta select ively inhibits CD3-CD28 costimulation, but not tumor necrosis factor alpha- induced activation of NF-kappa B in Jurkat T cells. The induction of NF-kap pa B by PKC-theta is mediated through the activation of I kappa B kinase be ta (IKK beta) in the absence of detectable IKK alpha stimulation. PKC-theta acts directly or indirectly to stimulate phosphorylation of IKK beta, lead ing to activation of this enzyme. Together, these results implicate PKC-the ta in one pathway of CD3-CD28 costimulation leading to NF-kappa B activatio n that is apparently distinct from that involving Cot and NF-kappa B-induci ng kinase (NIK). PKC-theta activation of NF-kappa B is mediated through the selective induction of IKK beta, while the Cot- and NIK-dependent pathway involves induction of both IKK alpha and IKK beta.