Low–molecular-weight hyaluronic acid induces nuclear factor-κB–dependent resistance against tumor necrosis factor α–mediated liver injury in mice



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. (HEPATOLOGY 2001;34:535-547.)