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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.
Highlights
Rheumatoid arthritis (RA), characterized by joint inflammation, synovial hyperplasia and excessive bone resorption, is mediated by many immune cells and inflammatory cytokines
The results revealed that both IL-17A and IL-17F expression in the Th17-polarized cells was significantly suppressed by etanercept (0.1 and 1 μg/mL) and adalimumab (1 and 10 μg/mL) after 5 days of Th17 polarization (Figure 1C and 1D)
We demonstrated that IL-17A and IL-17F production by normal Th17-polarized cells were significantly suppressed by both etanercept and adalimumab
Summary
Rheumatoid arthritis (RA), characterized by joint inflammation, synovial hyperplasia and excessive bone resorption, is mediated by many immune cells and inflammatory cytokines. The frequency of Th17 cells is reportedly higher in peripheral blood mononuclear cells from patients with RA than healthy subjects [2]. Adalimumab (HumiraTM) is a human anti-human TNF-α antibody. Both etanercept and adalimumab have been approved by the U.S Food and Drug Administration (FDA) for human use to prevent inflammatory processes in RA. In RA patients treated with TNF-α inhibitors, serum Th17-related cytokines decreased significantly in parallel with clinical remission in the responders, whereas increased percentage of Th17 cell and elevating related cytokine levels were found in non-responders [6, 7]. Mechanisms of how these TNF-α inhibitors suppress cytokine production, especially the immunomodulatory effects on Th17 cells, are yet to be elucidated
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