Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses

Abstract

Biological agents have dramatically improved treatment options for patients with severe psoriasis. Etanercept (tumor necrosis factor [TNF] receptor–immunoglobulin fusion protein) is an effective treatment for many psoriasis patients, and blockade of TNF is considered to be its primary action. However, in this clinical trial, we show that etanercept has early inhibitory effects on a newly appreciated type of T cells: T helper type 17 (Th17) cells. Etanercept reduced the inflammatory dendritic cell products that drive Th17 cell proliferation (interleukin [IL] 23), as well as Th17 cell products and downstream effector molecules (IL-17, IL-22, CC chemokine ligand 20, and β-defensin 4). In contrast, Th1 cellular products and effector molecules (interferon γ, lymphotoxin α, and myxovirus resistance 1) were reduced late in disease resolution. This study suggests a role for Th17 in addition to Th1 cells in the pathogenesis of psoriasis. Th17 cells may be particularly important in driving epidermal activation in psoriatic plaques, whereas Th1 cells must also be eliminated for final disease resolution.

Restoring the balance: Harnessing regulatory T cells for therapy in rheumatoid arthritis

“…Anti-TNF may directly inhibit Th17 through its known inhibitory effects on IL-1 and IL-6 production in RA [24]. Indeed etanercept, another anti-TNF agent, has been shown to inhibit Th17 cells in patients with psoriasis [25]. Therapy with infliximab has also been associated with a reduction in the rate of Treg apoptosis in patients with RA [26], although it is unclear whether this is a direct effect or indirectly perhaps through the alteration of the cytokine milieu.…”

Imunopatogênese da psoríase

“…Therefore, cytokines Th17 stimulate the keratinocytes to proliferate and to produce inumerous inflammatory proteins (Pic.1). 1,5,7,8 The proliferation of LTh1 induced by IL-12 leads to the production of TNF-α and INF-γ. The INF-γ also stimulates the production of IL-12, IL-8, IP-10, IL-23, defensins and iNOS by the keratinocytes and DC.…”

“…The INF-γ also stimulates the production of IL-12, IL-8, IP-10, IL-23, defensins and iNOS by the keratinocytes and DC. [7][8] Interferons, TNFs and IL-20 are activators of transcription factors (STAT-1, STAT-3 and nuclear factor κB) that, in their turn, control various groups of genes that codify various inflammatory mediators in psoriasis. 1,5,9 Recent studies in patients treated with etanercept reveal that the TNF modulates the activation and maturation of the DCs in psoriasis.…”

“…1,5,9 Recent studies in patients treated with etanercept reveal that the TNF modulates the activation and maturation of the DCs in psoriasis. 7,8 The blocking of TNF by this therapeutic agent decreases the activation and maturation of the Dcs and consequently inhibts the activation of the lymphocytes and the production of cytokines, chemokines and growth factors by LT, DC keratinocytes 7,8 It is worth mentioning that the IL-6, the TNF-· and the IL-17 are cytokines involved in the pathogenesis of the atherosclerosis, what justifies a higher incidence of cardiovascular diseases and of the metabolic syndrome in patients with psoriasis. 2,10 Concluding this study, the knowledge of the main alterations between the SII and the SIA is essential for a better understanding of the immunopathogenesis of psoriasis, as well as of the mechanisms of action of the immunosupressive and biological medications used in its treatment.…”

Current progress in γδ T-cell biology

“…63 However, the role of IL-17 in cutaneous wound healing, and whether it is produced by skin cd T cells, are less clear. Here, Büchau and colleagues reported that cultured skin cd T cells rapidly produce IL-17A upon TCR activation.…”