Cytokeratin 8 protects from hepatotoxicity, and its ratio to cytokeratin 18 determines the ability of hepatocytes to form mallory bodies

In alcoholic hepatitis, a severe form of alcohol-induced toxic liver injury , as well as in experimental intoxication of mice with the porphyrinogenic drugs griseofulvin and 3,5-diethoxycarbonyl-1,4-dihydrocollidine, hepatocyt es form cytoplasmic protein aggregates (Mallory bodies; MBs) containing cyt okeratins (CKs) and non-CK components. Here we report that mice lacking the CK8 gene and hence CK intermediate filaments in hepatocytes, but still exp ressing the type I partner, ie, the CK18 gene, do not form MBs but suffer f rom extensive porphyria and progressive toxic Liver damage, leading to the death of a considerable number of animals (7 of 12 during 12 weeks of intox ication). Our observations show that 1) in the absence of CK8 as well as in the situation of a relative excess of CK18 over CK8 no MBs are formed; 2) the loss of CK8 is not compensated by other type II CKs; and 3) porphyria a nd toxic Liver damage are drastically enhanced in the absence of CK8. Our r esults point to a protective role of CKs in certain types of toxic liver in jury and suggest that MBs by themselves are not harmful to hepatocytes but may be considered as a product of a novel defense mechanism in hepatocytes.