211 Concanavalin A-Induced Hepatitis in Mice Is Prevented by Depletion of Gut Bacteria Using Antibiotics

Abstract

L or hyposmotic conditions, as measured by LDH and HMGB1 release. Upon hyposmotic stress of hepatocytes, cell death occurred in the absence of caspase activation. Similar to primary hepatocytes, K18-DE mice treated with Fas-L had elevated serum necrosis markers (LDH and HMGB1) as compared to their WT counterparts. K18-DE mutation renders the K18 obligate heteropolymer, K8, less susceptible to phosphorylation at its p38 stress kinase site K8 S79, without altering the binding of K8/K18 to p38 kinase. Notably, K8 S79 phosphorylation plays an important role in mediating keratin filament reorganization upon stress. Conclusions: Caspase digestion of K18 plays an essential role in promoting apoptosisassociated keratin filament collapse in the liver. Keratin phosphorylation-mediated filament reorganization appears to be critical in protecting hepatocytes from necroapoptosis, and provides a mechanism for susceptibility to tissue injury in human IF mutations that involve caspase cleavage sites.