Protein kinase C and calcineurin synergize to activate I kappa B kinase and NF-kappa B in T lymphocytes

The nuclear factor of kappa B (NF-kappa B) is a ubiquitous transcription fa ctor that is key in the regulation of the immune response and inflammation. T cell receptor (TCR) cross-linking is in part required for activation of NF-kappa B, which is dependent on the phosphorylation and degradation of I kappa B alpha. By using Jurkat and primary human T lymphocytes, we demonstr ate that the simultaneous activation of two second messengers of the TCR-in itiated signal transduction, protein kinase C (PKC) and calcineurin, result s in the synergistic activation of the I kappa B alpha kinase (IKK) complex but not of another putative I kappa B alpha kinase, p90(rsk). We also demo nstrate that the IKK. complex, but not p90(rsk), is responsible for the in vivo phosphorylation of I kappa B alpha mediated by the co-activation of PK C and calcineurin, Each second messenger is necessary, as inhibition of eit her one reverses the activation of the IKK complex and I kappa B alpha phos phorylation in vivo, Overexpression of dominant negative forms of IKK alpha and -beta demonstrates that only IKK beta is the target for PKC and calcin eurin, These results indicate that within the TCR/CD3 signal transduction p athway both PKC and calcineurin are required for the effective activation o f the IKK complex and NF-kappa B in T lymphocytes.