期刊
ANTIOXIDANTS & REDOX SIGNALING
卷 35, 期 11, 页码 885-903出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/ars.2019.7835
关键词
imperatorin; neutrophil; PDE4 inhibitor; psoriasis; superoxide anion
资金
- Ministry of Science Technology, Taiwan [MOST 106-2320-B-255-003-MY3, MOST 104-2320-B-255-004-MY3, MOST 106-2320-B-182A-002-MY2, MOST 107-2320-B182A-003]
- Ministry of Education, Taiwan [EMRPD1G0231, EMRPD1H0381]
- Chang Gung Memorial Hospital, Taiwan [CMRPF1F0011-3, CMRPF1F0061-3, CMRPF1G0241-3, CMRPG3G1201, BMRP450]
- Chang Gung University of Science and Technology, Taiwan [ZRRPF3H0101, ZRRPF3H0111]
The research demonstrates that imperatorin inhibits human neutrophil functions by elevating cAMP/PKA, alleviating symptoms in psoriasis models, and potentially serving as a new therapeutic option for neutrophilic psoriasis.
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.
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