The Histone Deacetylase Inhibitor ITF2357 Reduces Production of Pro-Inflammatory Cytokines In Vitro and Systemic Inflammation In Vivo

Abstract

We studied inhibition of histone deacetylases (HDACs), which results in the unraveling of chromatin, facilitating increased gene expression. ITF2357, an orally active, synthetic inhibitor of HDACs, was evaluated as an anti-inflammatory agent. In lipopolysaccharide (LPS)-stimulated cultured human peripheral blood mononuclear cells (PBMCs), ITF2357 reduced by 50% the release of tumor necrosis factor-α (TNFα) at 10 to 22 nM, the release of intracellular interleukin (IL)-1α at 12 nM, the secretion of IL-1β at 12.5 to 25 nM, and the production of interferon-γ (IFNγ) at 25 nM. There was no reduction in IL-8 in these same cultures. Using the combination of IL-12 plus IL-18, IFNγ and IL-6 production was reduced by 50% at 12.5 to 25 nM, independent of decreased IL-1 or TNFα. There was no evidence of cell death in LPS-stimulated PBMCs at 100 nM ITF2357, using assays for DNA degradation, annexin V, and caspase-3/7. By Northern blotting of PBMCs, there was a 50% to 90% reduction in LPS-induced steady-state levels of TNFα and IFNγ mRNA but no effect on IL-1β or IL-8 levels. Real-time PCR confirmed the reduction in TNFα RNA by ITF2357. Oral administration of 1.0 to 10 mg/kg ITF2357 to mice reduced LPS-induced serum TNFα and IFNγ by more than 50%. Anti-CD3-induced cytokines were not suppressed by ITF2357 in PBMCs either in vitro or in the circulation in mice. In concanavalin-A-induced hepatitis, 1 or 5 mg/kg of oral ITF2357 significantly reduced liver damage. Thus, low, nonapoptotic concentrations of the HDAC inhibitor ITF2357 reduce pro-inflammatory cytokine production in primary cells in vitro and exhibit anti-inflammatory effects in vivo.

Protective Effects of Epigenetic Modifications in Experimental Inflammatory Bowel Disease

“…Currently, the focus has changed to the anti-inflammatory impact of these agents [40]. Several experimental models have revealed the anti-inflammatory effects of HDIs, including LPS-induced shock, concanavalin A-induced hepatitis [20], murine models of systemic lupus erythematosus [30], arthritis [41] and ovalbumin-induced airway inflammation [42]. Our own data in models of experimental colitis further support the concept that inhibition of HDAC is associated with an antiinflammatory effect.…”

“…In addition to these studies, there is increasing evidence for an additional anti-inflammatory potency of HDIs [17][18][19][20].…”

“…The anti-inflammatory efficacy of HDAC could be demonstrated in various in vivo models including concanavalin A-induced hepatitis, LPS-induced shock, experimental autoimmuneencephalomyelitisandvarious modelsofexperimentalcolitis [17,19,20,30]. As outlined in section 20.1, inflammatory bowel disease is a chronic disease accompanying patients throughout their life.…”

Valproic acid attenuates inflammation in experimental autoimmune neuritis

“…Further, it is established that helper T cell differentiation and a variety of related cytokine expression accompany histone acetylation pattern remodeling [43,44]. HDAC inhibitors effectively reduced the expression of pro-inflammatory cytokines, IFN-g, TNF-a, IL-1b, IL-12 and IL-6 [45,46]. IL-17 and IL-17F expression is also related to changes in histone acetylation [47].…”

The Therapeutic Potential of Epigenetics in Autoimmune Diseases

“…The main anti-inflammatory property of HDACIs is the reduced production of cytokines (TNF-α, IL-1β, IL-6, INF-γ) [148][149][150], chemokines (CXCL-9, CXCL-10, CXC-11) [151], and related receptors (IL-8R) [150,152]. Although controversial, these actions seem to be mediated by a downregulation of the NFκB transactivating activity through the hyperacetylation of the molecule or of other proteins involved in its phosphorylation cascade [146,153], and by the acetylation of STAT3 [154].…”