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Deacetylase Activity Is Required for STAT5-Dependent GM-CSF Functional Activity in Macrophages and Differentiation to Dendritic Cells¹

Institute for Research in Biomedicine and University of Barcelona, Barcelona, Spain

After interaction with its receptor, GM-CSF induces phosphorylation of the β-chain in two distinct domains in macrophages. One induces activation of mitogen-activated protein kinases and the PI3K/Akt pathway, and the other induces JAK2-STAT5. In this study we describe how trichostatin A (TSA), which inhibits deacetylase activity, blocks JAK2-STAT5-dependent gene expression but not the expression of genes that depend on the signal transduction induced by the other domain of the receptor. TSA treatment inhibited the GM-CSF-dependent proliferation of macrophages by interfering with c-myc and cyclin D1 expression. However, M-CSF-dependent proliferation, which requires ERK1/2, was unaffected. Protection from apoptosis, which involves Akt phosphorylation and p21^waf-1 expression, was not modified by TSA. GM-CSF-dependent expression of MHC class II molecules was inhibited because CIITA was not induced. The generation of dendritic cells was also impaired by TSA treatment because of the inhibition of IRF4, IRF2, and RelB expression. TSA mediates its effects by preventing the recruitment of RNA polymerase II to the promoter of STAT5 target genes and by inhibiting their expression. However, this drug did not affect STAT5A or STAT5B phosphorylation or DNA binding. These results in GM-CSF-treated macrophages reveal a relationship between histone deacetylase complexes and STAT5 in the regulation of gene expression.

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¹ This work was supported by a grant from the Ministerio de Ciencia y Tecnología BFU2004-05725/BMC and BFU2007-63712/BMC.

² Address correspondence and reprint requests to Dr. Antonio Celada, Institute for Research in Biomedicine, Barcelona Science Park, Josep Samitier 1-5, 08028 Barcelona, Spain. E-mail address: acelada{at}ub.edu

³ Abbreviations used in this paper: HAT, histone acetyl transferase; ChIP, chromatin immunoprecipitation; DC, dendritic cell; GAS, -IFN-activated sequence; HDAC, histone deacetylase; IRF, IFN regulatory factor; si, small interfering; TSA, trichostatin A.