Histone deacetylase inhibitor Trichostatin A reduces anti-DNA autoantibody production and represses IgH gene transcription.
Systemic lupus erythematosus is characterized by the presence of autoantibodies and hypergammaglobulinemia. To investigate the role of histone deacetylases (HDACs) in the production of autoantibody and immunoglobulin, we examined the effect of Trichostatin A (TSA), a specific inhibitor of HDACs, on anti-DNA autoantibody production and IgH gene transcription. Our results showed that inhibition of HDAC activity by TSA markedly reduced anti-DNA autoantibody production by T347 cells either by inducing apoptosis or in an apoptosis-independent manner, suggesting that TSA might be useful for treating certain autoimmune diseases. Moreover, we found that TSA strongly inhibited germline and post-switch immunoglobulin transcripts in T347 cells and in primary splenic B cells of MRL-lpr mice. Reporter gene analysis demonstrated that both Emu and 3'-IgH enhancer activities were repressed significantly by TSA-mediated HDAC inhibition. Furthermore, we observed that HDAC1 was recruited to the 3'-IgH enhancer hs1,2 as determined by chromatin immunoprecipitation assays. Over-expression of HDAC1 increased the activity of IgH enhancers, especially 3'-IgH enhancers. These findings implicate HDAC in the IgH gene transcription via activation of 3'-IgH enhancers.
Lu
Zhong-Ping
ZP
Shanghai Institute of Immunology, Shanghai Second Medical University, Shanghai 200025, People's Republic of China.
Ju
Zhong-Liang
ZL
Shi
Guang-Yin
GY
Zhang
Jing-Wu
JW
Sun
Jian
J
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis*; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004742:Enhancer Elements, Genetic; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D051379:Mice; D014158:Transcription, Genetic / Q000187:drug effects*
D000974:Antibodies, Antinuclear; D017931:DNA Primers; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007143:Immunoglobulin Heavy Chains; C012589:trichostatin A