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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.Acute pancreatitis was induced by choline-deficient ethionine diet in C57/BL6 (TLR4+/+ and TLR4−/−) mice.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 < .01 versus controls. In TLR4−/− mice with pancreatitis, PKC-ζ mRNA and activity were reduced, ERK1/2 and caspase-3 did not increase, and NF-κB and TUNEL (mostly in hepatocytes) increased mildly (all P < .01 vs control). PKC-ζ did not interact directly with NF-κB; however, during pancreatitis, coimmunoprecipitation of PKC-ζ with ERK1/2 was increased in TLR4+/+ mice and was attenuated in TLR4−/− mice (all P < .01 vs control), indicating that PKC-ζ interacts with ERK1/2.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.