Here we have addressed the role that zetaPKC plays in NF-kappaB activation using mice in which this kinase was inactivated by homologous recombination. These mice, although grossly normal, showed phenotypic alterations in secondary lymphoid organs reminiscent of those of the TNF receptor-1 and of the lymphotoxin-beta receptor gene-deficient mice. The lack of zetaPKC in embryonic fibroblasts (EFs) severely impairs kappaB-dependent transcriptional activity as well as cytokine-induced phosphorylation of p65. Also, a cytokine-inducible interaction of zetaPKC with p65 was detected which requires the previous degradation of IkappaB. Although in zetaPKC-/- EFs this kinase is not necessary for IKK activation, in lung, which abundantly expresses zetaPKC, IKK activation is inhibited.
Asthma is a disease of chronic airway inflammation in which T helper (Th) 2 cells play a critical role. The molecular mechanisms controlling Th2 differentiation and function are of paramount importance in biology and immunology. PKC has been implicated in the regulation of apoptosis and NF-B, as well as in the control of T-dependent responses, although no defects were detected in naïve T cells from PKC ؊/؊ mice. Here, we report that PKC is critical for IL-4 signaling and Th2 differentiation. Thus, PKC levels are increased during Th2 differentiation, but not Th1 differentiation, of CD4 ؉ T cells, and the loss of PKC impairs the secretion of Th2 cytokines in vitro and in vivo, as well as the nuclear translocation and tyrosine phosphorylation of Stat6 and Jak1 activation, essential downstream targets of IL-4 signaling. Moreover, PKC ؊/؊ mice display dramatic inhibition of ovalbumin-induced allergic airway disease, strongly suggesting that PKC can be a therapeutic target in asthma.apoptosis ͉ asthma ͉ NF-B
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