The immunomodulatory effects of TNF-α inhibitors on human Th17 cells via RORγt histone acetylation

Abstract

The presence of interleukin (IL)-17-related cytokines correlates with rheumatoid arthritis (RA) pathogenesis. Epigenetic modifications, including histone acetylation, regulate gene expression in RA pathogenesis. Tumour necrosis factor-alpha (TNF-α) inhibitors such as etanercept and adalimumab, represent a breakthrough in RA treatment. We aimed to investigate the effects of etanercept and adalimumab on human Th17-polarized cells and the possible intracellular regulators of these effects, including the Th17-specific transcription factors signal transducer, activator of transcription 3 (STAT3), retinoid-related orphan receptor γ-T (RORγt) and epigenetic modification. Human CD4+ T cells from healthy subjects and patients with RA were pretreated with TNF-α inhibitors and then being polarized into IL-17-producing cells. The Th17-related cytokine levels in the culture supernatants were determined with an enzyme-linked immunosorbent assay. Intracellular signalling was investigated by western blot, real-time RT-PCR, and chromatin immunoprecipitation. Th17-polarized cells from patients with RA produced more IL-17A, IL-17F and IL-22 than those from healthy subjects. Etanercept and adalimumab suppressed IL-17A, IL-17F and IL-22 levels in Th17-polarized cells from healthy subjects and patients with RA. Western blot analysis revealed that etanercept and adalimumab decreased mitogen-activated protein kinase-phospho-p38, nuclear factor-κB-phospho-p65, phospho-STAT3 and RORγt levels. Etanercept and adalimumab decreased histone (H)3 and H4 acetylation in the RORγt gene promotor region by decreasing the recruitment of the acetyltransferases p300, CBP and PCAF. The present study broadens our knowledge of the mechanisms underlying the immunomodulatory effects of TNF-α inhibitors in rheumatoid arthritis treatment.

Differentiation stage-specific effect of histone deacetylase inhibitors on the expression of RORγT in human lymphocytes

“…The importance of HDAC activity in the regulation of the Rorgt gene was recently demonstrated using conditional knockout mice: Hdac3 was shown to be necessary for the inhibition of Rorgt gene expression during thymocyte-positive selection [30]. Using TNF-a inhibitors, as well as anacardic acid (an acetyltransferase inhibitor), Lin et al [34] were able to down-regulate Rorgt expression in a process associated with a decrease in histone acetylation in its promoter. Additionally, Chen et al [29] showed that Hdac1 and Hdac2 occupy the mouse Rorgt promoter at the ER element.…”

“…Relatively little is known about the epigenetic pathways involved in the regulation of human RORC. However, Schmidl et al [33] have shown that the RORC locus is methylated in cells with low expression of RORC, and there is increasing evidence that the gene is also regulated by histone acetylation [29,34].…”

Rejection of intestinal allotransplants is driven by memory T helper type 17 immunity and responds to infliximab

“…Although we cannot rule out additive anti–TNF‐α effects of steroids in our study, our observed efficacy of infliximab treatment in patients with severe allograft rejection refractory to treatment could also be related to more specific mechanisms of targeting Th17 cells via TNF‐α inhibition. These have been described and include blockade of RORγt, the lineage defining transcription factor for Th17 cells, 37 as well as overall inhibition of IL‐17 and TNF‐α production in both activated CD4 + cells but specifically polarized Th17 cells 38 . These mechanisms have been established in autoimmune models.…”

Increased p300/CBP expression in acute respiratory distress syndrome is associated with interleukin‐17 and prognosis

“…Therefore, p300/ CBP may be a potential therapeutic target for interventions against IL-17. 31,32 In the past few decades, although many studies have focused on the potential function of p300 and CBP in human disease, these have focused on cancer, chronic inflammation and other diseases. 33,34 Few studies have demonstrated a role for p300 and CBP in ARDS patients.…”