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Received Dec 19, 2017; Revised Mar 28, 2018; Accepted Apr 17, 2018
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1. Introduction
Psoriasis, affecting 2-3% of the worldwide population, is an inflammatory, chronic skin disease considered to be an immune-mediated one. It is characterized by excessive proliferation and abnormal differentiation, accompanied by apoptosis of keratinocytes (KCs) causing erythematous, scaly patches, or plaques on the skin [1–3]. In the psoriatic skin area, expression of proinflammatory cytokines and chemokines is upregulated, attracting immune cells leading to the proliferation of local and invading cells [4]. The proinflammatory cytokine interleukin-23 (IL-23) is one of the major cytokines involved in the pathogenesis of psoriasis [5] by mediating Th17 cells, which release interleukin-17 (IL-17) into the inflamed environment. IL-23 is highly expressed in psoriatic skin and is secreted among other cells, also from KCs [6]. Its blockade by injection of specific human anti-IL-23 antibody results in neutralizing IL-23 and prevention of disease progression in psoriasis patients [7]. High levels of IL-17 have been detected in psoriatic skin lesions [8, 9], strengthening the assumption that inhibition of both cytokines will result in improvement of disease pathology.
A3 adenosine receptor (A3AR) is a Gi protein-coupled cell surface receptor, known to mediate anti-inflammatory effects upon activation with selective agonists. The A3AR was found to be highly expressed in inflammatory tissues [10, 11] and in the peripheral blood mononuclear cells (PBMCs) [12–14] of patients with Crohn’s disease, psoriasis, and rheumatoid arthritis (RA). The mechanism responsible for receptor overexpression suggests the involvement of the transcription factors nuclear factor kappa B (NF-κB) and cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), both present in the A3AR gene promotor and are known to be upregulated in psoriasis [12]. It was found that the inflammatory cytokine tumor necrosis factor α (TNF-α) regulates A3AR via an autocrine pathway while an increase in this cytokine expression results in a subsequent increase in NF-κB and receptor upregulation [13].
Piclidenoson is an A3AR highly specific agonist, inducing a robust anti-inflammatory effect demonstrated in preclinical...