HDACi and Inflammatory Cells

Early studies showed that hydroxamate-based pan-HDACi compounds, such as TsA, SAHA and similar agents, have inhibitory effects on cytokine production by LPS-treated monocytes cultured in vitro (Table 1) as well as in mice injected

Table 1 Effects of HDACi on cells in vitro

Cells

Stimulus

HDACi

Effect of HDACi

PBMC M0

PBMC PBMC

LPS or IFN-g

IL-12 and IL-18 CD3/CD28 mAb

Th1/Th2 clones

Antigen-pulsed DC

ITF2357 (Leoni et al. 2005) Butyrate (Saemann et al. 2000), NVP-LAQ824 (Brogdon et al. 2007), TsA (Han and Lee 2009) SAHA (Leoni et al. 2002),

ITF2357 (Leoni et al. 2005) SAHA (Leoni et al. 2002), ITF2357 (Leoni et al. 2005) TsA, scriptaid, oxamflatin, butyrate and other HDACi (Edens et al. 2006)

NVP-LAQ824 (Brogdon et al. 2007)

Decreased expression of many cytokines and chemokines, and upregulation of IL-10

Decreased TNF-a, IFN-g, IL-6

No effect on IL-2, IFN-g or GM-CSF production by primary T cells, but impaired proliferation and IL-2 and IFN-g production and increased anergy using Th1 clones

Impaired Th1-linked chemokines (CXCR3 ligands) but preserved IL-4 and Th2 chemokines (CCR4 ligands); impaired Th1 but not Th2 proliferation; and impaired IFN-g but not IL-4 production

Abbreviations: DC dendritic cells, mAb monoclonal antibody, M0 monocyte-derived macrophages ± DC, PBMC peripheral blood mononuclear cells with LPS, acting to dampen monocyte production of TNF-a, IL-1a, and IL-1p (Leoni et al. 2002, 2005). Moreover, hydroxamate compounds typically did not affect CD3 mAb-induced proliferation of primary T cells when used at physiologic doses that do not induce apoptosis (Leoni et al. 2002, 2005). These early data of the effects of HDACi on monokine production and macrophage activation have been confirmed (Han and Lee 2009) and extended to additional areas in subsequent studies. Thus, synovial macrophages and intact synovial tissue samples from patients with rheumatoid arthritis showed decreased cytokine production (IL-6, TNF-a) and increased apoptosis when exposed to TsA in vitro (Grabiec et al. 2010). These data are consistent with the upregulation of HDAC expression by LPS and increased expression of proinflammatory genes, such as COX-2, though which combination of HDACs are upregulated appears to vary by cell type and, more broadly, by proinflammatory stimulus (Aung et al. 2006; Suen et al. 2010). By contrast to their effects on monocytes and dendritic cells, the effects of HDACi on T-cell responses are more nuanced than initially appeared, with evidence of HDACi impairing generation of signals 2 (costimulatory molecules) and 3 (activating cytokines) in antigen-pulsed antigen-presenting cells and associated impairment of the proliferation and chemotaxis of Th1 but not Th2 cells (Brogdon et al. 2007; Jung et al. 2009).

Table 2 Effects of HDACi in vivo

Model

HDACi

Effect of HDACi

Arthritis

Butyrate (Chung et al. 2003),

Protective effects in collagen- or

Depsipeptide (Nishida et al. 2004;

antibody-induced arthritis

Nakamura et al. 2005) MS-275

(Lin et al. 2007) SAHA (Lin et al.

2007), TsA (Chung et al. 2003),

VPA (Saouafetal. 2009)

Asthma

TsA (Choi et al. 2005a)

Decreased airway hyperresponsiveness and inflammation

CD3 mAb

SAHA (Leoni et al. 2002), ITF2357 (Leoni et al. 2005)

No effect on IL-2 or IFN-g

Colitis

VPA and SAHA (Glauben et al. 2006)

Protective effects in DSS and TNBS models

EAE, EAN

TsA (Camelo et al. 2005; Gray and

Reduced disability scores during chronic

Dangond 2006), MS-275 (Zhang

relapsing EAE, reduced

et al. 2010a)

inflammation in autoimmune neuritis model

GVHD

SAHA (Leng et al. 2006; Reddy

Decreased inflammation and improved

et al. 2004; Li et al. 2008)

donor cell engraftment

Hepatitis

SAHA (Leoni et al. 2002), ITF2357

Decreased liver injury in Con-A

(Leoni et al. 2005)

hepatitis

Hypertension

SAHA (Iyer et al. 2010), VPA

Decreased BP, inflammatory cytokine

(Cardinale et al. 2010)

expression, cardiac hypertrophy and myocardial fibrosis in spontaneously hypertensive or DOCA-salt fed rats

LPS

SAHA (Leoni et al. 2002), ITF2357 (Leoni et al. 2005)

Decreased TNF-a IL-1P, IL-6, IFN-g

Lupus

TsA and SAHA (Mishra et al. 2003)

Decreased IL-12, IFN-g, IL-6, IL-10, proteinuria and glomerulo-nephritis but not autoantibody production or IgG or C3 deposition in MRL-lpr/lpr

Sepsis

Butyrate (Zhang et al. 2010b), SAHA

Decreased lethality and sepsis-related

(Li et al. 2009; Halili et al. 2010;

liver, lung and muscle injury

Finkelstein et al. 2010; Li et al.

2010), TsA (Zhang et al. 2010b;

Halili et al. 2010; Alamdari

et al. 2010)

UUO

TsA or VPA (Marumo et al. 2010)

Decreased renal tubulointerstitial injury after ureteric obstruction

Rodent models unless specified; abbreviations: EAE experimental allergic encephalomyelitis, EAN experimental allergic neuritis, GVHD graft versus host disease, LPS lipopolysaccharide, UUO unilateral ureteric obstruction

Rodent models unless specified; abbreviations: EAE experimental allergic encephalomyelitis, EAN experimental allergic neuritis, GVHD graft versus host disease, LPS lipopolysaccharide, UUO unilateral ureteric obstruction

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