Deletion of toll-like receptor-4 downregulates protein kinase C-ζ and attenuates liver injury in experimental pancreatitis

Background Toll-like receptor-4 (TLR4) and protein kinase C-zeta (PKC-ζ) play a role in macrophage activation. We hypothesized that deletion of TLR4 downregulates PKC-ζ and attenuates liver cell apoptosis in experimental pancreatitis. Methods Acute pancreatitis was induced by choline-deficient ethionine diet in C57/BL6 (TLR4+/+ and TLR4−/−) mice. Results During pancreatitis, staining for TLR4 and PKC-ζ, which colocalized in Kupffer cells but not in hepatocytes, increased in TLR4+/+ mice and decreased in TLR4−/− mice. In TLR4+/+ mice, pancreatitis increased TLR4 protein and mRNA and PKC-ζ protein and activity, nuclear factor (NF)-κB, ERK1/2, caspase-3 cleavage, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining; all P P P Conclusion Acute pancreatitis upregulates TLR4, PKC-ζ, NF-κB, and ERK1/2, and increases apoptosis in mice livers. PKC-ζ induces nuclear translocation of NF-κB via ERK1/2-dependent mechanisms. Deletion of TLR4 downregulates PKC-ζ, NF-κB, and ERK1/2, and attenuates pancreatitis-induced liver cell apoptosis.