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Crosstalk between PKCζ and the IL4/Stat6 pathway during T‐cell‐mediated hepatitis
Author(s) -
Durán Angeles,
Rodriguez Angelina,
Martin Pilar,
Serrano Manuel,
Flores Juana Maria,
Leitges Michael,
DiazMeco María T,
Moscat Jorge
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600468
Subject(s) - biology , crosstalk , interleukin 4 , stat6 , microbiology and biotechnology , signal transduction , immunology , cytokine , physics , optics
PKCζ is required for nuclear factor κ‐B (NF‐κB) activation in several cell systems. NF‐κB is a suppressor of liver apoptosis during development and in concanavalin A (ConA)‐induced T‐cell‐mediated hepatitis. Here we show that PKCζ−/− mice display inhibited ConA‐induced NF‐κB activation and reduced damage in liver. As the IL‐4/Stat6 pathway is necessary for ConA‐induced hepatitis, we addressed here the potential role of PKCζ in this cascade. Interestingly, the loss of PKCζ severely attenuated serum IL‐5 and liver eotaxin‐1 levels, two critical mediators of liver damage. Stat6 tyrosine phosphorylation and Jak1 activation were ablated in the liver of ConA‐injected PKCζ−/− mice and in IL‐4‐stimulated PKCζ−/− fibroblasts. PKCζ interacts with and phosphorylates Jak1 and PKCζ activity is required for Jak1 function. In contrast, Par‐4−/− mice have increased sensitivity to ConA‐induced liver damage and IL‐4 signaling. This unveils a novel and critical involvement of PKCζ in the IL‐4/Stat6 signaling pathway in vitro and in vivo .