Crosstalk between PKCzeta and the IL4/Stat6 pathway during T-cell-mediated hepatitis.
PKCzeta is required for nuclear factor kappa-B (NF-kappaB) activation in several cell systems. NF-kappaB is a suppressor of liver apoptosis during development and in concanavalin A (ConA)-induced T-cell-mediated hepatitis. Here we show that PKCzeta-/- mice display inhibited ConA-induced NF-kappaB 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 PKCzeta in this cascade. Interestingly, the loss of PKCzeta 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 PKCzeta-/- mice and in IL-4-stimulated PKCzeta-/- fibroblasts. PKCzeta interacts with and phosphorylates Jak1 and PKCzeta 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 PKCzeta in the IL-4/Stat6 signaling pathway in vitro and in vivo.
Durán
Angeles
A
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain.
Rodriguez
Angelina
A
Martin
Pilar
P
Serrano
Manuel
M
Flores
Juana Maria
JM
Leitges
Michael
M
Diaz-Meco
María T
MT
Moscat
Jorge
J
D000818:Animals; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000378:metabolism; D003208:Concanavalin A; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D015847:Interleukin-4 / Q000502:physiology*; D015848:Interleukin-5 / Q000097:blood; D053613:Janus Kinase 1; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D018179:Receptors, Thrombin / Q000235:genetics / Q000378:metabolism; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D015534:Trans-Activators / Q000502:physiology*; D000099221:Protein Kinase C zeta
D054413:Chemokine CCL11; D019742:Chemokines, CC; D003208:Concanavalin A; D015847:Interleukin-4; D015848:Interleukin-5; D053613:Janus Kinase 1; D016328:NF-kappa B; D011493:Protein Kinase C; D011505:Protein-Tyrosine Kinases; D018179:Receptors, Thrombin; D050800:STAT6 Transcription Factor; D015534:Trans-Activators; D000099221:Protein Kinase C zeta; C515457:Ccl11 protein, mouse; C494100:Stat6 protein, mouse; C507905:Jak1 protein, mouse; C112908:protease-activated receptor 4