KUPFFER CELL DEPLETION PARTIALLY PREVENTS HEPATIC HEME OXYGENASE-1 MESSENGER-RNA ACCUMULATION IN SYSTEMIC INFLAMMATION IN MICE - ROLE OF INTERLEUKIN-1-BETA

The heme oxygenase 1 (HO-1) gene is rapidly activated in the liver aft er lipopolysaccharide (LPS) treatment. Ninety minutes after LPS treatm ent (0.1 mg/kg, intraperitoneally) hepatic HO-1 messenger RNA (mRNA) o f mice was 40 times the control value, To investigate the hepatic cell ular source of the increased HO-1 transcript, we treated mice with LPS and galactosamine (700 mg/kg, intraperitoneally), a selective transcr iptional inhibitor of hepatocytes. Galactosamine prevented the LPS-med iated increase of HO-1 mRNA in the liver, indicating that hepatocytes are the main cell type in which HO-1 mRNA accumulates after LPS treatm ent. We then tested in vitro and in vivo the hypothesis that LPS-media ted hepatic accumulation of HO-1 mRNA is caused by intercellular commu nication between Kupffer cells and hepatocytes, Isolated rat hepatocyt es showed an increase in HO-1 mRNA compared with controls after 90 min utes of exposure to a LPS stimulated Kupffer cell-conditioned medium. This suggests that soluble mediators from Kupffer cells were responsib le for this effect. To study the role of Kupffer cells in vivo, we tre ated mice with Kupffer cell-inactivating or -depleting agents and LPS. Gadolinium chloride and liposome-encapsulated dichloromethylene dipho sphonate lowered LPS-mediated HO-1 mRNA accumulation (by about 50%); i n these groups hepatic levels of interleukin (IL)-1 beta were decrease d, by more than 75%, Methylpalmitate hardly affected hepatic HO-1 mRNA accumulation or IL-1 beta content after LPS treatment. There was no r elationship between HO-1 mRNA and serum TNF or IL-6 levels. These resu lts suggest that LPS-mediated hepatic HO-1 mRNA accumulation is a hepa tocyte response partly caused by soluble mediators, particularly IL-1 beta, released from Kupffer cells.