These insights, coupled with new tools for targeting transcription factors and chromatin-modifying proteins (Table 1), suggest that small-molecule modulators of transcription will be useful for therapeutic manipulation of cytokine networks. RORγt (retinoid-related orphan receptor γt) is a nuclear hormone receptor (NHR) implicated in CD by human genetics that promotes differentiation of TH17 cells (Figure 1d) [23• and 40]. Although a monoclonal antibody targeting IL-17A (secukinumab) has demonstrated potential for treating psoriasis and ankylosing spondylitis, it is ineffective in CD patients [41]. The failure of IL-17A blockade in CD may suggest the need to suppress a

wider set of cytokines produced by TH17 cells, possibly by interfering with TH17 differentiation. RORγt contains a deep binding pocket for endogenous small-molecule ligands, which has facilitated development of RORγt selleck antagonists that suppress TH17 cell differentiation and display efficacy in murine models of graft-versus-host disease, demyelinating neurological disorders and cutaneous inflammation [42 and 43•]. Their established roles in immune cell IWR-1 price function, coupled with

their ability to bind small molecules, make other NHRs intriguing drug targets. Activation of the retinoic acid receptor (RAR) by vitamin A metabolites enhances development of anti-inflammatory CD4+ regulatory T cells (Tregs), an effect that contributes to the therapeutic activity of all-trans retinoic acid in murine models of autoimmune disease [44]. Binding of the aryl hydrocarbon receptor (AhR) by the tryptophan metabolite kynurenine stimulates IL-10 production by DCs and promotes Treg differentiation [45 and 46]; two mechanisms that may underlie the finding that sub-lethal doses of bacteria enhance resistance to subsequent infections [47]. NHRs often work in concert with chromatin-modifying enzymes,

several classes of which have been targeted with small molecules to modulate cytokine production. The novel small-molecule inhibitor of the Jumonji family histone demethylases JMJD3 and UTX (GSK-J4) suppresses inflammatory cytokine production in macrophages [48••]. Histone deacetylase (HDAC) inhibitors targeting multiple isoforms suppress inflammatory cytokine production by macrophages, promote Treg Celecoxib differentiation and display efficacy in murine models of inflammation [49]. Of note, physiological concentrations of the microbial metabolite and pan-HDAC inhibitor butyrate specifically suppress IL-6, IL-12 and nitric oxide production in gut macrophages suggesting that HDAC inhibition may serve to limit autoinflammatory responses to commensal microbes [13]. While Hdac3−/− murine macrophages display reduced inflammatory cytokine production [ 50], selective deletion of HDAC3 in intestinal epithelial cells alters intestinal architecture and increases sensitivity to experimentally induced colitis [ 51].