Aim: Neutrophil infiltration and increased oxidative stress are involved in the pathogenesis and severity of
psoriasis. Although the
therapy of
psoriasis remains elusive, targeting treatment to reduce oxidative stress is considered a potential option. Our study demonstrates the anti-inflammatory effects of a natural
furocoumarin,
imperatorin, on activated human neutrophils and psoriasiform
dermatitis in mice. Results:
Imperatorin inhibited
superoxide anion generation, neutrophil adhesion, and migration in N-formyl-l-methionyl-l-leucyl-
l-phenylalanine (fMLF)-stimulated human neutrophils. Further studies showed that
imperatorin induced a decrease in cAMP-specific
phosphodiesterase (PDE) activity, and increased intracellular cAMP levels and
protein kinase A (PKA) activity in human neutrophils. The
enzyme activities of PDE4 subtypes, but not PDE3 and PDE7, were inhibited by
imperatorin. Furthermore,
imperatorin inhibited the phosphorylation of
protein kinase B (Akt), extracellular regulated
kinase (ERK), and
c-Jun N-terminal kinase (JNK), as well as Ca2+ mobilization in fMLF-stimulated neutrophils. These suppressive effects of
imperatorin on cell responses and signaling were reversed by
PKA inhibitor, suggesting that cAMP/PKA is involved in the anti-inflammatory effects of
imperatorin. In vivo studies of
imiquimod- and interleukin-23-induced mouse psoriasiform
dermatitis demonstrated that
imperatorin alleviated skin desquamation, epidermal thickening, keratinocyte hyperproliferation, and neutrophil infiltration. Innovation and Conclusion: Our results demonstrate that
imperatorin inhibits human neutrophil respiratory burst, adhesion, and migration through the elevation of cAMP/PKA to inhibit Akt, ERK, JNK, and Ca2+ mobilization.
Imperatorin is a natural inhibitor of PDE4A/B/C and may serve as a lead for developing new
therapeutics to treat neutrophilic
psoriasis. Antioxid. Redox Signal. 35, 885-903.