Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase–dependent DC functions and regulates experimental graft-versus-host disease in mice
Pavan Reddy, … , Charles A. Dinarello, James L.M. Ferrara
Pavan Reddy, … , Charles A. Dinarello, James L.M. Ferrara
Published June 20, 2008
Citation Information: J Clin Invest. 2008;118(7):2562-2573. https://doi.org/10.1172/JCI34712.
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Research Article Immunology

Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase–dependent DC functions and regulates experimental graft-versus-host disease in mice

Abstract

Histone deacetylase (HDAC) inhibitors are antitumor agents that also have antiinflammatory properties. However, the mechanisms of their immunomodulatory functions are not known. We investigated the mechanisms of action of 2 HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and ITF 2357, on mouse DC responses. Pretreatment of DCs with HDAC inhibitors significantly reduced TLR-induced secretion of proinflammatory cytokines, suppressed the expression of CD40 and CD80, and reduced the in vitro and in vivo allostimulatory responses induced by the DCs. In addition, injection of DCs treated ex vivo with HDAC inhibitors reduced experimental graft-versus-host disease (GVHD) in a murine allogeneic BM transplantation model. Exposure of DCs to HDAC inhibitors increased expression of indoleamine 2,3-dioxygenase (IDO), a suppressor of DC function. Blockade of IDO in WT DCs with siRNA and with DCs from IDO-deficient animals caused substantial reversal of HDAC inhibition–induced in vitro suppression of DC-stimulated responses. Direct injection of HDAC inhibitors early after allogeneic BM transplantation to chimeric animals whose BM-derived cells lacked IDO failed to protect from GVHD, demonstrating an in vivo functional role for IDO. Together, these data show that HDAC inhibitors regulate multiple DC functions through the induction of IDO and suggest that they may represent a novel class of agents to treat immune-mediated diseases.

Authors

Pavan Reddy, Yaping Sun, Tomomi Toubai, Raimon Duran-Struuck, Shawn G. Clouthier, Elizabeth Weisiger, Yoshinobu Maeda, Isao Tawara, Oleg Krijanovski, Erin Gatza, Chen Liu, Chelsea Malter, Paolo Mascagni, Charles A. Dinarello, James L.M. Ferrara

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Figure 1

Effect of HDAC inhibitors on LPS-induced secretion of proinflammatory cytokines by BMDCs.

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Effect of HDAC inhibitors on LPS-induced secretion of proinflammatory cy...
DCs were obtained from C57BL/6 animals as described in Methods. BMDCs were preincubated for 16–20 h with indicated concentrations of SAHA or diluent and were then stimulated overnight with LPS (100 ng/ml). Proinflammatory cytokines levels in the supernatants were measured by ELISA. (A) TNF-α levels. (B) IL-12 levels. (C) IL-6 levels. *P < 0.02 versus stimulated control DCs. (D) DCs were pretreated with the indicated concentrations of SAHA and ITF 2357 or diluent as described in A. TNF-α levels were measured in the supernatants after overnight stimulation with LPS. **P < 0.01 versus stimulated control DCs. (E) Macrophages (F4/80+) were obtained from C57BL/6 mice after peritoneal lavage and pretreated with SAHA or diluent for 14–16 h. They were then stimulated overnight with LPS, and TNF-α from the culture supernatant was measured. *P < 0.02 versus control macrophages. Data (mean ± SEM) are from 1 of 2–3 experiments with similar results. Unlabeled bar(s) at left represent unstimulated controls.