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Cutting Edge: Negative Regulation of Dendritic Cells through Acetylation of the Nonhistone Protein STAT-3¹

Yaping Sun^*, Y. Eugene Chin, Elizabeth Weisiger^*, Chelsea Malter^*, Isao Tawara^*, Tomomi Toubai^*, Erin Gatza^*, Paolo Mascagni, Charles A. Dinarello and Pavan Reddy^2,*

^* Department of Internal Medicine and University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109; Department of Surgery, Brown University Medical School, Providence, RI 02912; Italfarmaco, Cinisello Balsamo, Italy; and Department of Medicine, University of Colorado Health Sciences, Denver, CO 80045

Histone deacetylase (HDAC) inhibition modulates dendritic cell (DC) functions and regulates experimental graft-vs-host disease and other immune-mediated diseases. The mechanisms by which HDAC inhibition modulates immune responses remain largely unknown. STAT-3 is a transcription factor shown to negatively regulate DC functions. In this study we report that HDAC inhibition acetylates and activates STAT-3, which regulates DCs by promoting the transcription of IDO. These findings demonstrate a novel functional role for posttranslational modification of STAT-3 through acetylation and provide mechanistic insights into HDAC inhibition-mediated immunoregulation by induction of IDO.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI-075284 (to P.R.), HL-090775 (to P.R.), AI-15614 (to C.A.D.), and HL-68743 (to C.A.D.). P.R. is a recipient of the Alaina J. Enlow Scholar Award and the Doris Duke Clinical Scientist Development Award.

² Address correspondence and reprint requests to Dr. Pavan Reddy, 6310 Comprehensive Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0942. E-mail address: reddypr{at}umich.edu

³ Abbreviations used in this paper: HDAC, histone deacetylase; ChIP, chromatin immunoprecipitation; DC, dendritic cell; GAS, gamma-activated sequence; SAHA, suberoylanilide hydroxamic acid.

⁴ The online version of this article contains supplemental material.