Abstract
Interleukin-17 and interleukin-23 play major roles in the inflammatory process in psoriasis. The Gi protein-associated A3 adenosine receptor (A3AR) is known to be overexpressed in inflammatory cells and in peripheral blood mononuclear cells (PBMCs) of patients with autoimmune inflammatory conditions. Piclidenoson, a selective agonist at the A3AR, induces robust anti-inflammatory effect in psoriasis patients. In this study, we aimed to explore A3AR expression levels in psoriasis patients and its role in mediating the anti-inflammatory effect of piclidenoson in human keratinocyte cells. A3AR expression levels were evaluated in skin tissue and PBMCs derived from psoriasis patients and healthy subjects. Proliferation assay and the expression of signaling proteins were used to evaluate piclidenoson effect on human keratinocytes (HaCat). High A3AR expression levels were found in a skin biopsy and in PBMCs from psoriasis patients in comparison to healthy subjects. Piclidenoson inhibited the proliferation of HaCat cells through deregulation of the NF-κB signaling pathway, leading to a decrease in interleukin-17 and interleukin-23 expression levels. This effect was counteracted by the specific antagonist MRS 1523. A3AR overexpression in skin and PBMCs of psoriasis patients may be used as a target to inhibit pathological cell proliferation and the production of interleukin-17 and interleukin-23.
Highlights
Psoriasis, affecting 2-3% of the worldwide population, is an inflammatory, chronic skin disease considered to be an immune-mediated one
Polyclonal antibodies against human A3 adenosine receptor (A3AR), phosphoinositide 3-kinase (PI3K), NF-κB, tumor necrosis factor α (TNF-α), IL-17, IL-23, and β-actin were purchased from Santa Cruz Biotechnology Inc., Ca, USA
A3AR Is Overexpressed in Skin Tissue and peripheral blood mononuclear cells (PBMCs) of Psoriasis Patients
Summary
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 [1,2,3]. 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]. 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
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