Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis

Schafer, P.H. et al. (2010) Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. British Journal of Pharmacology, 159(4), pp. 842-855. (doi: 10.1111/j.1476-5381.2009.00559.x)

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Abstract

<b>Background and purpose</b>: Apremilast is an orally administered phosphodiesterase-4 inhibitor, currently in phase 2 clinical studies of psoriasis and other chronic inflammatory diseases. The inhibitory effects of apremilast on pro-inflammatory responses of human primary peripheral blood mononuclear cells (PBMC), polymorphonuclear cells, natural killer (NK) cells and epidermal keratinocytes were explored in vitro, and in a preclinical model of psoriasis. <b>Experimental approach</b>: Apremilast was tested in vitro against endotoxin- and superantigen-stimulated PBMC, bacterial peptide and zymosan-stimulated polymorphonuclear cells, immunonoglobulin and cytokine-stimulated NK cells, and ultraviolet B light-activated keratinocytes. Apremilast was orally administered to beige-severe combined immunodeficient mice, xenotransplanted with normal human skin and triggered with human psoriatic NK cells. Epidermal skin thickness, proliferation index and inflammation markers were analysed. <b>Key results</b>: Apremilast inhibited PBMC production of the chemokines CXCL9 and CXCL10, cytokines interferon-γ and tumour necrosis factor (TNF)-α, and interleukins (IL)-2, IL-12 and IL-23. Production of TNF-α by NK cells and keratinocytes was also inhibited. In vivo, apremilast significantly reduced epidermal thickness and proliferation, decreased the general histopathological appearance of psoriasiform features and reduced expression of TNF-α, human leukocyte antigen-DR and intercellular adhesion molecule-1 in the lesioned skin. <b>Conclusions and implications</b>: Apremilast displayed a broad pattern of anti-inflammatory activity in a variety of cell types and decreased the incidence and severity of a psoriasiform response in vivo. Inhibition of TNF-α, IL-12 and IL-23 production, as well as NK and keratinocyte responses by this phosphodiesterase-4 inhibitor suggests a novel approach to the treatment of psoriasis.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Houslay, Professor Miles and Baillie, Professor George and Cheung, Miss York-fong
Authors: Schafer, P.H., Parton, A., Gandhi, A.K., Capone, L., Adams, M., Wu, L., Bartlett, J.B., Loveland, M.A., Gilhar, A., Cheung, Y.-F., Baillie, G.S., Houslay, M.D., Man, H.-W., Muller, G.W., and Stirling, D.I.
Subjects:R Medicine > R Medicine (General)
Q Science > QH Natural history > QH301 Biology
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
Journal Name:British Journal of Pharmacology
ISSN:0007-1188
ISSN (Online):1476-5381
Published Online:24 December 2009
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