Phosphodiesterase-4 inhibitors reduce the expression of proinflammatory mediators by human epidermal keratinocytes independent of intracellular cAMP elevation

Abstract

Cyclic adenosine monophosphate (cAMP) acts as a second messenger for intercellular signal transduction. In particular, the cAMP-PKA-CREB pathway is crucial for the regulation of inflammatory genes in immune cells. To target that pathway in immune responses, phosphodiesterase 4 (PDE4) inhibitors that inhibit the conversion of cAMP to AMP were developed. [ [1] Li H. Zuo J. Tang W. Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases. Front. Pharmacol. 2018; 9: 1048 Crossref PubMed Scopus (215) Google Scholar ] Apremilast, a PDE4 inhibitor, was approved for the oral treatment of psoriasis and psoriatic arthritis. Additionally, a modest efficacy of apremilast for atopic dermatitis (AD) has been shown [ [2] Simpson E.L. Imafuku S. Poulin Y. Ungar B. Zhou L. Malik K. Wen H.C. Xu H. Estrada Y.D. Peng X. Chen M. Shah N. Suarez-Farinas M. Pavel A.B. Nograles K. Guttman-Yassky E. A phase 2 randomized trial of apremilast in patients with atopic dermatitis. J. Invest. Dermatol. 2019; 139: 1063-1072 Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar ]. Crisaborole, another PDE4 inhibitor, was approved for the topical treatment of AD [ [3] Zebda R. Paller A.S. Phosphodiesterase 4 inhibitors. J. Am. Acad. Dermatol. 2018; 78: S43-s52 Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar ] and has also been reported to be effective for psoriasis [ [4] Lee E.B. Lebwohl M.G. Wu J.J. Treatment of psoriasis with crisaborole. J. Dermatolog. Treat. 2019; 30: 156-157 Crossref PubMed Scopus (11) Google Scholar , [5] Moustafa F. Feldman S.R. A review of phosphodiesterase-inhibition and the potential role for phosphodiesterase 4-inhibitors in clinical dermatology. Dermatol. Online J. 2014; 20: 22608 PubMed Google Scholar ]. Roflumilast, another PDE4 inhibitor, has been used for chronic obstructive pulmonary disease. [ [1] Li H. Zuo J. Tang W. Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases. Front. Pharmacol. 2018; 9: 1048 Crossref PubMed Scopus (215) Google Scholar ] Mechanistically, PDE4 inhibitors down-regulate the expression of TNFα, IL-17A and IL-23 but up-regulate IL-10 in immune cells such as macrophages and T lymphocytes. [ [1] Li H. Zuo J. Tang W. Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases. Front. Pharmacol. 2018; 9: 1048 Crossref PubMed Scopus (215) Google Scholar , [6] Guttman-Yassky E. Hanifin J.M. Boguniewicz M. Wollenberg A. Bissonnette R. Purohit V. Kilty I. Tallman A.M. Zielinski M.A. The role of phosphodiesterase 4 in the pathophysiology of atopic dermatitis and the perspective for its inhibition. Exp. Dermatol. 2019; 28: 3-10 PubMed Google Scholar ] The effect of PDE4 inhibitors on normal human epidermal keratinocytes (NHEKs) has not been reported except for two studies, in which apremilast suppressed ultraviolet B induced-TNFα [ [7] 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. Stirling D.I. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br. J. Pharmacol. 2010; 159: 842-855 Crossref PubMed Scopus (301) Google Scholar ] but not CXCL8 production [ [8] Furue K. Ito T. Tanaka Y. Yumine A. Hashimoto-Hachiya A. Takemura M. Murata M. Yamamura K. Tsuji G. Furue M. Cyto/chemokine profile of in vitro scratched keratinocyte model: implications of significant upregulation of CCL20, CXCL8 and IL36G in Koebner phenomenon. J. Dermatol. Sci. 2019; 94: 244-251 Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar ]. Here, we explored the impact of three PDE4 inhibitors on NHEKs in more detail.