Phosphodiesterase 4 in inflammatory diseases: Effects of apremilast in psoriatic blood and in dermal myofibroblasts through the PDE4/CD271 complex

Abstract

Phosphodiesterases 4 (PDE4) act as proinflammatory enzymes via degradation of cAMP, whereas PDE4 inhibitors play an anti-inflammatory role in vitro and in vivo. In particular, apremilast has been recently approved for the treatment of psoriasis and psoriatic arthritis. However, little is known on the expression pattern of PDE4 in psoriasis. We report that PDE4B and PDE4D mRNA are overexpressed in peripheral blood mononuclear cells (PBMC) from psoriasis, as compared with normal controls, while apremilast reduces PBMC production of a number of pro-inflammatory cytokines and increases the levels of anti-inflammatory mediators. PDE4 expression is up-regulated in psoriatic dermis as compared with normal skin, with particular regard to fibroblasts. This is confirmed in vitro, where both dermal fibroblasts (DF) and, to a greater extent, myofibroblasts (DM) express all PDE4 isoforms at the mRNA and protein level. Because PDE4 interacts with the nerve growth factor (NGF) receptor CD271 in lung fibroblasts, we evaluated the relationship and function of PDE4 and CD271 in normal human skin fibroblasts. All PDE4 isoforms co-immunoprecipitate with CD271 in DM, while apremilast inhibits apoptosis induced by β-amyloid, a CD271 ligand, in DM. Furthermore, apremilast significantly reduces NGF- and transforming growth factor-β1 (TGF-β1)-induced fibroblast migration, and inhibits DF differentiation into DM mediated by NGF or TGF-β1. Finally, in DM, apremilast significantly reduces cAMP degradation induced by treatment with β-amyloid. Taken together, these results indicate that PDE4 play an important role in psoriasis. In addition, the study reveals that the PDE4/CD271 complex could be important in modulating fibroblast functions.

Psoriasis vulgaris associated with systemic lupus erythematosus successfully treated with apremilast

“…The Cutaneous LE Disease Area and Severity Index showed a significant decrease after 85 days of treatment with apremilast 20 mg twice daily in eight patients with active discoid LE. Furthermore, Schafer et al 4 revealed that PDE4 isoform D was increased versus normal controls in peripheral blood mononuclear cells from patients with both psoriasis and SLE. Although we cannot rule out the possibility that the skin lesions of our patient were papulosquamous type erythema of SLE because we did not perform the skin biopsy ourselves, our case report suggests that apremilast may be a new treatment option for patients with coexistent psoriasis and SLE.…”

p75 Neurotrophin Receptor in the Skin: Beyond Its Neurotrophic Function

“…In addition, NGF or BDNF increase the tensile strength in a collagen gel (35), while tensile stimuli increase NGF in human fibroblasts (36). Recently, p75 NTR has been shown to co-immunoprecipitate with the pro-inflammatory phosphodiesterases-4 in myofibroblasts (37), although the activities of this complex remain to be clarified.…”

Inhibition of phosphodiesterase‐4 attenuates murine ulcerative colitis through interference with mucosal immunity

“…PDE4 is highly specific for cAMP degradation, and elevation of intracellular cAMP by PDE4 inhibition contributes to suppression of cell trafficking and to the release of chemokines and cytokines from inflammatory cells. Lower levels of colon cAMP and up-regulation of PDE4 expression were observed in IBD, which resulted in abnormal production of cytokines in the inflamed intestine (Banner & Trevethick, 2004;Schafer et al, 2016). Given the suppression of inflammatory cytokines following PDE4 inhibition, compounds such as rolipram, tetomilast, and roflumilast have been applied to experimental models of colitis (El-Ashmawy, Khedr, El-Bahrawy, & El-Adawy, 2018;Hartmann et al, 2000;Ichikawa et al, 2008).…”