title: Largazole, a class I histone deacetylase inhibitor, enhances TNF-α-induced ICAM-1 and VCAM-1 expression in rheumatoid arthritis synovial fibroblasts.
abstract: In the present study, we evaluated the effect of largazole (LAR), a marine-derived class I HDAC inhibitor, on tumor necrosis factor-α (TNF-α)-induced expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and matrix metalloproteinase-2 (MMP-2) activity. LAR (1-5 μM) had no adverse effect on the viability of RA synovial fibroblasts. Among the different class I HDACs screened, LAR (0.5-5 μM) inhibited the constitutive expression of HDAC1 (0-30%). Surprisingly, LAR increased class II HDAC [HDAC6] by ~220% with a concomitant decrease in HDAC5 [30-58%] expression in RA synovial fibroblasts. SAHA (5 μM), a pan-HDAC inhibitor, also induced HDAC6 expression in RA synovial fibroblasts. Pretreatment of RA synovial fibroblasts with LAR further enhanced TNF-α-induced ICAM-1 and VCAM-1 expression. However, LAR inhibited TNF-α-induced MMP-2 activity in RA synovial fibroblasts by 35% when compared to the TNF-α-treated group. Further, the addition of HDAC6 specific inhibitor Tubastatin A with LAR suppressed TNF-α+LAR-induced ICAM-1 and VCAM-1 expression and completely blocked MMP-2 activity, suggesting a role of HDAC6 in LAR-induced ICAM-1 and VCAM-1 expression. LAR also enhanced TNF-α-induced phospho-p38 and phospho-AKT expression, but inhibited the expression of phospho-JNK and nuclear translocation of NF-κBp65 in RA synovial fibroblasts. These results suggest that LAR activates p38 and Akt pathways and influences class II HDACs, in particular HDAC6, to enhance some of the detrimental effects of TNF-α in RA synovial fibroblasts. Understanding the exact role of different HDAC isoenzymes in RA pathogenesis is extremely important in order to develop highly effective HDAC inhibitors for the treatment of RA.
authors: Department of Pharmacology, College of Pharmacy & Pharmaceutical Sciences, The University of Toledo, Health Science Campus, Toledo, OH 43614, USA. Salah.Ahmed@utoledo.edu
authors: Salahuddin
authors: S
authors: Ahmed
authors: Sharayah
authors: S
authors: Riegsecker
authors: Maria
authors: M
authors: Beamer
authors: Ayesha
authors: A
authors: Rahman
authors: Joseph V
authors: JV
authors: Bellini
authors: Pravin
authors: P
authors: Bhansali
authors: L M Viranga
authors: LM
authors: Tillekeratne
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D047630:Depsipeptides / Q000494:pharmacology*; D004357:Drug Synergism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D012313:RNA / Q000737:chemistry / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013844:Thiazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D011994:Recombinant Proteins; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C527895:largazole; D018799:Intercellular Adhesion Molecule-1; D012313:RNA; D051058:Oncogene Protein v-akt; D048051:p38 Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2
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