HEAT-SHOCK IN-VIVO INDUCES MALLORY BODY FORMATION IN DRUG PRIMED MOUSE-LIVER

Perturbations in keratin intermediate filament organization and Mallor y body (MB) formation are associated with alcoholic hepatitis. Inducib le heat shock proteins (HSPs) are expressed in a variety of liver dise ases including alcoholic liver disease. Therefore, we investigated whe ther heat shock protein induction can lead to MB formation. Mice were primed by a 5-month feeding of griseofulvin (GF) or diethyl -dehydro-2 ,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC) followed by drug withdr awal for 1 month. The animals were then subjected to an in vivo heat s hock treatment or sham heat treatment. Liver morphology, HSP expressio n, liver regeneration (PCNA-labeled nuclei), and MB formation were mon itored during a 7-day posttreatment period. Numerous MBs developed in the livers of mice exposed to GF or DDC for 5 months, but very few sma ll MBs remained after 1-month withdrawal of either drug. No MBs were f ound at Day 1 post heat shock, whereas numerous MBs were observed at D ay 7. The frequency of PCNA-labeled nuclei increased during the same p eriod. At Day 1 posttreatment, a variable liver centrilobular necrosis was observed accompanied by a prominent increase in HSP-25 and HSP70 expression, but HSP-90 expression was not increased. In drug-primed mo use liver, a heat shock treatment induces the expression of specific H SPs prior to the formation of MBs, indicating that HSP expression may play a role in the pathogenesis of MB formation. We speculate that thi s role is through the protein unfolding function of HSP, which leads t o the aggregation of the cytokeratins to form MBs as well as to polyub iquitin binding to these proteins in a manner analogous to amyloid for mation. (C) 1995 Academic Press, Inc.