Low-molecular-weight hyaluronic acid induces nuclear factor-kappaB-dependent resistance against tumor necrosis factor alpha-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 alpha (TNF-alpha)-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-alpha to D-galactosamine (GalN)-sensitized mice. LMW-HA-induced hepatoprotection could be neutralized by pretreatment with the nuclear factor-kappaB (NF-kappaB) inhibitor, pyrrolidine dithiocarbamate (PDTC), demonstrating the involvement of NF-kappaB in the observed protective mechanism. Indeed, injection of LMW-HA rapidly induced the production of TNF-alpha by Kupffer cells and the translocation of NF-kappaB into hepatocellular nuclei. Both LMW-HA-induced TNF-alpha production and NF-kappaB 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-alpha- and NF-kappaB-dependent cytoprotective proteins within the target parenchymal liver cells.
Wolf
D
D
Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
Schümann
J
J
Koerber
K
K
Kiemer
A K
AK
Vollmar
A M
AM
Sass
G
G
Papadopoulos
T
T
Bang
R
R
Klein
S D
SD
Brüne
B
B
Tiegs
G
G
D036002:ADP Ribose Transferases; D000818:Animals; D001427:Bacterial Toxins; D018791:CD4 Lymphocyte Count; D016923:Cell Death / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000517:prevention & control*; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000097:blood; D005098:Exotoxins / Q000494:pharmacology; D018960:Hyaluronan Receptors / Q000032:analysis; D006820:Hyaluronic Acid / Q000737:chemistry* / Q000494:pharmacology*; D007728:Kupffer Cells / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000473:pathology; D017093:Liver Failure / Q000209:etiology / Q000517:prevention & control; D018655:Lymphocyte Count; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008970:Molecular Weight; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D003208:Concanavalin A; D016207:Cytokines; D005098:Exotoxins; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A