Histone deacetylase activities are required for innate immune cell control of Th1 but not Th2 effector cell function

Abstract

IntroductionHistone-modifying enzymes, such as histone acetyltransferases (HATs) and histone deacetylases (HDACs), are critical in controlling the dynamics of chromatin structure and function by regulating histone acetylation. This process is essential in modulating gene transcription through chromatin organization, and plays an important role in many key biological processes. 1 The perturbation of this process results in aberrant gene transcription and causes neoplasia and other diseases. 2 In general, increased histone acetylation is associated with transcription activation through relaxed chromatin structure, whereas decreased histone acetylation is associated with repression of transcription via chromatin condensation. Recently, an increasing number of nonhistone proteins such as p53, HSP90, and STAT3, for example, have been identified as substrates of HDACs, indicating a novel mechanism of action of HDACs in modulating gene function. 3 The classical HDAC gene family consists of 11 members, which fall into 2 classes. Class I HDACs (HDAC1, HDAC2, HDAC3, and HDAC8) are expressed ubiquitously, whereas the expression of class II HDACs (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10) is more restricted. 4 Small molecules capable of inhibiting both class I and II HDAC activities, such as suberoylanilide hydroxamic acid (SAHA), trichostatin (TSA), trapoxin, and others, induce general histone acetylation, and are promising anticancer agents. 3,5 In addition to their anticancer activities, several HDAC inhibitors (HDACi's) have been shown to be effective in selected immune disease models. For example, SAHA has been shown to reduce graft-versushost disease (GVHD) in a murine model of bone marrow transplantation 6 and block renal disease in MRL-lpr/lpr mice 7 ; TSA suppressed adjuvant-induced rheumatoid arthritis (RA) in rats 8 and reduced clinical symptoms in a murine model of multiple sclerosis (MS). 9 However, little is known about the cellular and molecular mechanisms governing the in vivo effects of HDACi's in these autoimmune models. Therefore, we set out to systematically investigate the cellular effects of LAQ824, a novel hydroxamic acid derivative with demonstrated clinical efficacy as an HDAC pan-inhibitor, 5,10 in immune responses, and to suggest a mechanistic rationale for using HDACi's in inflammatory diseases.Chronic inflammation is a physiologic state that underlies many diseases. 11 The inflammation cascade is usually initiated by immune or stress responses to environmental or endogenous stimuli, and it is tightly controlled by the activation and silencing of differentially expressed genes. Professional antigen-presenting cells (APCs), particularly macrophages and dendritic cells (DCs), are central players in the initiation of an inflammation cascade. They are the first line of defense in that they respond to diverse antigens, secrete cytokines and chemokines, modulate the expression of costimulatory molecules, and thereby instruct other innate and adaptive immune cells to mount appropriate responses. 12...

HDAC inhibitor reduces cytokine storm and facilitates induction of chimerism that reverses lupus in anti-CD3 conditioning regimen

“…It is not surprising that the addition of SAHA to the anti-CD3-conditioning regimen did not lead to induction of GVHD, even though SAHA is a chemoreagent, because unlike traditional chemoreagents that cause host tissue damage and release of proinflammatory cytokines and chemokines (1,4), SAHA inhibits the tissue release of the proinflammatory cytokines and chemokines (16)(17)(18). In addition, HDAC inhibitors similar to SAHA have been shown to augment the generation and function of FoxP3 ϩ regulatory T (Treg) cells (26) and modulate APC function to down regulate Th1 differentiation (27). Treg cells were shown to prevent GVHD (28), and Th1 cells were shown to mediate GVHD (1).…”

Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and β-cell protection

“…Pharmacological targeting of KDACs has also been reported to trigger important changes in DC subsets and function, which are fundamental in initiating modulation of the host immune system (3,14,15). Vorinostat-treated NOD mice showed slightly decreased levels of CD11c…”

Safety and efficacy of an oral histone deacetylase inhibitor in systemic‐onset juvenile idiopathic arthritis

“…There is increasing evidence that HDA inhibitors may also exhibit antiinflammatory properties (3). ITF2357 (recently named givinostat) is a hydroxamic acid containing an HDA inhibitor, which reduces the production and release of several proinflammatory cytokines (tumor necrosis factor ␣, interleukin-1␤ [⌱L-1␤], interferon-␥, IL-6, and IL-12) from human blood monocytes (4) as well as in models of autoimmune diseases and inflammation, including models of arthritis and synovial cell functions (5,6).…”