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Keratin 18 provides resistance to Fas‐mediated liver failure in mice
Author(s) -
Leifeld L.,
Kothe S.,
Söhl G.,
Hesse M.,
Sauerbruch T.,
Magin T. M.,
Spengler U.
Publication year - 2009
Publication title -
european journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.164
H-Index - 107
eISSN - 1365-2362
pISSN - 0014-2972
DOI - 10.1111/j.1365-2362.2009.02133.x
Subject(s) - apoptosis , tunel assay , caspase , keratin , antibody , biology , microbiology and biotechnology , programmed cell death , caspase 8 , immunology , cancer research , biochemistry , genetics
Background Keratins are intermediate filament proteins of epithelial cells with pivotal functions for cell integrity. They comprise keratins 18 [K18] and 8 [K8] in hepatocytes. Keratins are of major importance for an intact cellular microarchitecture and have protective functions in human liver diseases. In mice, K8 has been demonstrated to protect against Fas‐antibody‐induced liver failure by direct interaction with apoptotic regulators, while the role of K18 remains unresolved. Materials and methods We analysed effects of K18 deficiency on Fas‐induced liver failure in mice. We determined survival and analysed induction of apoptosis after injection of the agonistic Fas antibody Jo2 into K18 −/− and wild‐type control mice by TUNEL assay and fluorometrically analysed caspase‐3, ‐8 and ‐9 activities 1, 2 and 3 h after Jo2 injection. Results In K18 −/− mice, survival of Fas‐antibody treated mice was significantly shorter than that of wild‐type controls ( P = 0·02). However, shortened survival of K18 −/− mice was caused by increased hepatic damage but was not correlated to enhanced induction of apoptotic pathways, as neither numbers of TUNEL positive apoptotic cells nor activities of caspases‐3, ‐8 and ‐9 differed between K18 −/− and K18 +/+ mice at any point of time. Conclusion K18 −/− mice are significantly more susceptible to Fas‐antibody‐induced liver failure. The cytoprotective effect of K18 is not explained by a differential activation of caspases‐3, ‐8 and ‐9, suggesting that K18 does not directly interfere with apoptotic regulators. Importantly, however, K18 exerts significant protective functions by other mechanisms.