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Blocking T H 17‐polarizing cytokines by histone deacetylase inhibitors in vitro and in vivo
Author(s) -
Bosisio Daniela,
Vulcano Marisa,
Prete Annalisa,
Sironi Marina,
Salvi Valentina,
Salogni Laura,
Riboldi Elena,
Leoni Flavio,
Dinarello Charles A.,
Girolomoni Giampiero,
Sozzani Silvano
Publication year - 2008
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0708401
Subject(s) - histone deacetylase , proinflammatory cytokine , chemokine , biology , trichostatin a , histone deacetylase 2 , pharmacology , cancer research , microbiology and biotechnology , immune system , immunology , inflammation , biochemistry , histone , gene
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‐γ. 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‐γ 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.