Blocking TH17-polarizing cytokines by histone deacetylase inhibitors in vitro and in vivo.
Histone deacetylase (HDAC) inhibitors are small molecules inducing cell-cycle arrest, differentiation, and apoptosis, currently undergoing clinical trials as anticancer drugs. In addition, emerging evidence suggests HDAC inhibitors may have anti-inflammatory and immunomodulatory properties as well, although the molecular mechanisms remain poorly defined. Given the central role of dendritic cells (DC) in the induction and maintenance of the inflammatory and immune response, we investigated the effects of HDAC inhibitors on the maturation and activation of human monocyte-derived DC in the presence of LPS and IFN-gamma. Our results show that the production of T(H)1- and T(H)17-inducing cytokines, namely IL-12 and IL-23, was inhibited by trichostatin A (72% and 52%, respectively) and suberoylanilide hydroxamic acid (86% and 83%). Strikingly, HDAC inhibitors were effective if added simultaneously as well as after the proinflammatory challenge, and their effect was not associated to a reduction of expression or function of LPS/IFN-gamma receptors. These findings were confirmed in two different murine models. In addition, HDAC inhibitors selectively blocked the production of T(H)1-attracting chemokines CXCL9, CXCL10, and CXCL11. The reduction of T(H)1- and T(H)17-inducing cytokines as well as T(H)1-attracting chemokines may represent relevant mechanisms through which HDAC inhibitors at nonproapoptotic doses exert their immunomodulatory properties.
Bosisio
Daniela
D
Section of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnologies, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
Vulcano
Marisa
M
Del Prete
Annalisa
A
Sironi
Marina
M
Salvi
Valentina
V
Salogni
Laura
L
Riboldi
Elena
E
Leoni
Flavio
F
Dinarello
Charles A
CA
Girolomoni
Giampiero
G
Sozzani
Silvano
S
D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053759:Interleukin-23 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017471:Receptors, Interferon / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D000077337:Vorinostat; D000096743:Interferon gamma Receptor
D018925:Chemokines; D016207:Cytokines; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D007371:Interferon-gamma; D018664:Interleukin-12; D053759:Interleukin-23; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D017471:Receptors, Interferon; D000077337:Vorinostat; D000096743:Interferon gamma Receptor; C012589:trichostatin A
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