title: Correction of all-trans retinoic acid deficiency in alcoholic cirrhosis lessens the excessive inflammatory monocyte response: a translational study.
abstract: OBJECTIVE
  Patients with alcoholic liver disease (ALD) have vitamin A (VA) deficiency and an enhanced immune response associated with disease severity. All-trans retinoic acid (ATRA), a VA-active metabolite, has anti-inflammatory effects and its deficiency could contribute to the exacerbated proinflammatory reaction. The aim of this study was to investigate the effects of ATRA/VA deficiency and supplementation on the monocyte response in ALD.
  
  
  METHODS
  Vitamin A and ATRA plasma levels were quantified in ALD patients and healthy subjects (HS). The in vitro effect of ATRA on lipopolysaccharide (LPS)-induced TNF-α production by human peripheral blood mononuclear cells (PBMC) was assessed by ELISA and RT-PCR. The activation pattern of peritoneal macrophages (PerMΦ) and circulating monocytes isolated from VA-deficient mice and ALD patients, respectively, was evaluated by flow cytometry, quantification of TNF-α and NO2 production.
  
  
  RESULTS
  Alcoholic liver disease patients (n = 85) showed plasmatic VA deficiency that was correlated with scores of severity and with the hepatic venous pressure gradient. ATRA levels correlated significantly with VA levels. In vitro, ATRA pretreatment decreased the overproduction of TNF-α by LPS-stimulated PBMC of ALD patients. In vivo, VA deficiency in mice was associated with increased activation of PerMΦ, while oral ATRA supplementation normalized it.
  
  
  CONCLUSIONS
  For the first time, we show that VA/ATRA deficiencies in ALD patients are associated with disease severity. Furthermore, our data strongly suggest that the VA deficiency observed in ALD patients might participate in the pathophysiology of the disease by priming immune cells, and that ATRA supplementation could downregulate the deleterious proinflammatory state in cirrhosis and might thus be of therapeutic use.
authors.affiliation: Laboratory of Experimental Gastroenterology, ULB, Brussels, Belgium; Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, ULB, Brussels, Belgium.
authors.forename: Romy
authors.initials: R
authors.lastname: Ouziel
authors.forename: Eric
authors.initials: E
authors.lastname: Trépo
authors.forename: Anneline
authors.initials: A
authors.lastname: Cremer
authors.forename: Christophe
authors.initials: C
authors.lastname: Moreno
authors.forename: Delphine
authors.initials: D
authors.lastname: Degré
authors.forename: Mustapha
authors.initials: M
authors.lastname: Chaouni
authors.forename: Vincent
authors.initials: V
authors.lastname: Vercruysse
authors.forename: Eric
authors.initials: E
authors.lastname: Quertinmont
authors.forename: Jacques
authors.initials: J
authors.lastname: Devière
authors.forename: Arnaud
authors.initials: A
authors.lastname: Lemmers
authors.forename: Thierry
authors.initials: T
authors.lastname: Gustot
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008104:Liver Cirrhosis, Alcoholic / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D014212:Tretinoin / Q000097:blood* / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014801:Vitamin A / Q000097:blood; D014802:Vitamin A Deficiency / Q000150:complications*
chemical_list: D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014801:Vitamin A; D014212:Tretinoin
keywords: ATRA; alcoholic hepatitis; alcoholic liver disease; tumour necrosis factor-α; vitamin A; vitamin A deficiency