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Low–molecular‐weight hyaluronic acid induces nuclear factor‐κB–dependent resistance against tumor necrosis factor α–mediated liver injury in mice
Author(s) -
Wolf Dominik,
Schümann Jens,
Koerber Kerstin,
Kiemer Alexandra K.,
Vollmar Angelika M.,
Sass Gabriele,
Papadopoulos Thomas,
Bang Renate,
Klein Sabine D.,
Brüne Bernhard,
Tiegs Gisa
Publication year - 2001
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2001.27218
Subject(s) - hyaluronic acid , liver injury , tumor necrosis factor alpha , necrosis , medicine , tumor necrosis factor α , cancer research , pathology , chemistry , endocrinology , anatomy
Liver resident NK1.1 + T cells are supposed to play a pivotal role in the onset of inflammatory liver injury in experimental mouse models such as concanavalin A (Con A)‐induced hepatitis. These cells, expressing the adhesion receptor, CD44, are largely depleted from the liver by a single intravenous injection of low‐molecular‐weight fragments of hyaluronic acid (LMW‐HA). Here, we report that LMW‐HA pretreatment protected mice from liver injury in several models of T‐cell– and macrophage‐dependent, tumor necrosis factor α (TNF‐α)‐mediated inflammatory liver injury, i.e., from liver injury induced by either Con A or Pseudomonas exotoxin A (PEA) or PEA/lipopolysaccharide (LPS). Interestingly, apart from inhibition of cellular adhesion, pretreatment of mice with LMW‐HA was also capable of preventing hepatocellular apoptosis and activation of caspase‐3 induced by direct administration of recombinant murine (rmu) TNF‐α to D ‐galactosamine (GalN)‐sensitized mice. LMW‐HA–induced hepatoprotection could be neutralized by pretreatment with the nuclear factor‐κB (NF‐κB) inhibitor, pyrrolidine dithiocarbamate (PDTC), demonstrating the involvement of NF‐κB in the observed protective mechanism. Indeed, injection of LMW‐HA rapidly induced the production of TNF‐α by Kupffer cells and the translocation of NF‐κB into hepatocellular nuclei. Both LMW‐HA–induced TNF‐α production and NF‐κB translocation were blocked by pretreatment with PDTC. Our findings provide evidence for an unknown mechanism of LMW‐HA–dependent protection from inflammatory liver disease, i.e., induction of TNF‐α– and NF‐κB–dependent cytoprotective proteins within the target parenchymal liver cells. (H EPATOLOGY 2001;34:535‐547.)