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

Motomura, Kenta, Mitsuru Ohata, Michael Satre, and Hidekazu Tsukamoto. Destabilization of TNF-a mRNA by retinoic acid in hepatic macrophages: implications for alcoholic liver disease. Am J Physiol Endocrinol Metab 281: E420–E429, 2001.—Retinoic acid (RA) inhibits hepatic macrophage (HM) cytokine expression, and retinoids are depleted in alcoholic liver disease (ALD). However, neither the causal link between the two nor the mechanism underlying RA-mediated HM inhibition is known. The aim of the present study was to determine the mechanism of RA-induced inhibition of HM tumor necrosis factor (TNF)-a expression and the relevance of this regulation to ALD. Treatment with all-trans RA (500 nM) caused a 50% inhibition in lipopolysaccharide (LPS)-stimulated TNF-a expression by cultured normal rat HM. The mRNA levels for inducible nitric oxide synthase, interleukin (IL)-6, IL-1a, and IL-1b were also reduced, whereas those for transforming growth factor-b1, MMP-9, and membrane cofactor protein-1 were unaffected. The inhibitory effect on TNF-a 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-a mRNA stability in HM. HM isolated from the ALD model showed significant decreases in all-trans RA (248%) and 9-cis RA (261%) contents, RA response element (RARE) binding, and mRNA levels for RARb, RXRa, and cytosolic retinol binding protein-1, whereas TNF-a mRNA expression was induced. TNF-a mRNA stability was increased in these cells, and an ex vivo treatment with all-trans RA normalized both RARb and TNF-a mRNA levels. These results demonstrate the RA-induced destabilization of TNF-a mRNA by cultured HM and the association of RA depletion with increased TNF-a mRNA stability in HM from experimental ALD. These findings suggest that RA depletion primes HM for proinflammatory cytokine expression in ALD, at least in part, via posttranscriptional regulation.