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

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] 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] Crisaborole, another PDE4 inhibitor, was approved for the topical treatment of AD [3] and has also been reported to be effective for psoriasis.[4,5] Roflumilast, another PDE4 inhibitor, has been used for chronic obstructive pulmonary disease.[1] Mechanistically, PDE4 inhibitors down-regulate the expression of TNF α, IL-17A and IL-23 but up-regulate IL-10 in immune cells such as macrophages and T lymphocytes.[1,6] 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] but not CX CL8 production.[8] Here, we explored the impact of three PDE4 inhibitors on NHEKs in more detail.
Source: Journal of Dermatological Science - Category: Dermatology Authors: Tags: Letter to the Editor Source Type: research