Destabilization of TNF-alpha mRNA by retinoic acid in hepatic macrophages:implications for alcoholic liver disease

Retinoic acid (RA) inhibits hepatic macrophage (HM) cytokine expression, an d retinoids are depleted in alcoholic liver disease (ALD). However, neither the causal link between the two nor the mechanism underlying RA-mediated H M inhibition is known. The aim of the present study was to determine the me chanism of RA-induced inhibition of HM tumor necrosis factor (TNF)-alpha ex pression and the relevance of this regulation to ALD. Treatment with all-tr ans RA (500 nM) caused a 50% inhibition in lipopolysaccharide (LPS)-stimula ted TNF-alpha expression by cultured normal rat HM. The mRNA levels for ind ucible nitric oxide synthase, interleukin (IL)-6, IL-1 alpha, and IL-1 beta were also reduced, whereas those for transforming growth factor-beta1, MMP -9, and membrane cofactor protein-1 were unaffected. The inhibitory effect on TNF-alpha expression was reproduced by LG268, a retinoid X receptor (RXR )-specific ligand, but not by TTNPB, an RA receptor (RAR)-specific ligand. RA did not alter LPS-stimulated NF-kB and activation protein-1 binding but significantly decreased TNF-alpha mRNA stability in HM. HM isolated from th e ALD model showed significant decreases in all-trans RA (-48%) and 9-cis R A (-61%) contents, RA response element (RARE) binding, and mRNA levels for RAR beta, RYR alpha, and cytosolic retinol binding protein-1, whereas TNF-a lpha mRNA expression was induced. TNF-alpha mRNA stability was increased in these cells, and an ex vivo treatment with all-trans RA normalized both RA R beta and TNF-alpha mRNA levels. These results demonstrate the RA-induced destabilization of TNF-alpha mRNA by cultured HM and the association of RA depletion with increased TNF-alpha mRNA stability in HM from experimental A LD. These findings suggest that RA depletion primes HM for proinflammatory cytokine expression in ALD, at least in part, via posttranscriptional regul ation.