Protein kinase C-zeta mediates apoptosis of mouse Kupffer cells via ERK-1/2: a novel mechanism.

Background We have demonstrated that activated Kupffer cells undergo accelerated apoptosis via Toll-like receptor (TLR)-4 and protein kinase C (PKC)-ζ–dependent nuclear factor (NF)-κB activation. Because PKC-ζ plays a pivotal role in cell signaling, we sought to determine the signaling pathway of PKC-ζ in Kupffer cell apoptosis. Methods Mouse Kupffer cell line (MKCL3-2) were transfected with PKC-ζ small interfering RNA (siRNA) and then treated with elastase alone or elastase along with the extracellular signal-regulated kinase (ERK) inhibitor U0126. Cell extracts were assayed for PKC-ζ (protein and activity), TLR-4, NF-κB nuclear translocation, phosphorylated ERK-1/2, activated caspase-3, and DNA fragmentation. All n ≥3; data are expressed as mean values ± standard deviations; means were compared using the t  test; P Results Elastase upregulated TLR-4, PKC-ζ, NF-κB, ERK-1/2, caspase-3, and DNA fragmentation (all P P Conclusion Activation of Kupffer cells upregulates PKC-ζ activity, increases apoptosis, and induces nuclear translocation of NF-κB via ERK-1/2–dependent pathways. Inhibiting the activity of PKC-ζ significantly attenuates Kupffer cell apoptosis, NF-κB, and ERK-1/2 activation. The interaction of PKC-ζ and ERK-1/2 warrants further investigation.