PMID- 36179418 OWN - NLM STAT- MEDLINE DCOM- 20221020 LR - 20221020 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 112 DP - 2022 Nov TI - Phellopterin alleviates atopic dermatitis-like inflammation and suppresses IL-4-induced STAT3 activation in keratinocytes. PG - 109270 LID - S1567-5769(22)00754-8 [pii] LID - 10.1016/j.intimp.2022.109270 [doi] AB - Anti-inflammation medication is one of the most important treatment for people with atopic dermatitis (AD) which presents persistent type 2 inflammation in skin lesions. Interaction between activated keratinocytes and immune cells in AD skin lesions amplifies inflammatory signaling by augmenting production of cytokines, such as keratinocyte-derived thymic stromal lymphopoietin (TSLP) and interleukin-33 (IL-33). Phellopterin is a bioactive compound isolated from ethanol extract of Angelica dahurica root which has been traditionally used for AD therapy in China. In the present study, we showed that Phellopterin possessed anti-type 2 inflammation activity and alleviated AD-like phenotypes including reduction in serum immunoglobulin E (IgE) levels and infiltration of eosinophils and mast cells in the AD-like skin lesions. Further molecular analysis found that Phellopterin suppressed phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr705, and the expression of TSLP and IL-33 in epidermal keratinocytes of AD-like lesions. In vitro studies in cultured human keratinocytes demonstrated that STAT3 was required for interleukin-4 (IL-4)-induced overexpression of TSLP and IL-33. Phellopterin inhibited IL-4-induced activation of STAT3, which leaded to suppress the STAT3-mediated transcription of TSLP and IL-33. Our study suggested that Phellopterin is an active compound with bioactivities of anti- type 2 inflammation and STAT3 inactivation, thus allowing to be a promising candidate for AD topical therapy. CI - Copyright (c) 2022 Elsevier B.V. All rights reserved. FAU - Chen, Xun AU - Chen X AD - Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu 610106, China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu 610106, China; School of Food and Biological Engineering, Chengdu University, Chengdu 610106, China. FAU - Zhang, Yujin AU - Zhang Y AD - Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu 610106, China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu 610106, China; School of Food and Biological Engineering, Chengdu University, Chengdu 610106, China. FAU - Pei, Junxia AU - Pei J AD - Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu 610106, China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu 610106, China; School of Food and Biological Engineering, Chengdu University, Chengdu 610106, China. FAU - Zeng, Xin AU - Zeng X AD - Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu 610106, China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu 610106, China; School of Pharmacy, Chengdu University, Chengdu 610106, China. FAU - Yang, Yixi AU - Yang Y AD - Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu 610106, China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu 610106, China; School of Food and Biological Engineering, Chengdu University, Chengdu 610106, China. FAU - Zhang, YaMei AU - Zhang Y AD - Key Laboratory of Clinical Genetics, Affiliated Hospital of Chengdu University, Chengdu 610106, China. FAU - Li, Fulun AU - Li F AD - Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, NO. 110, Ganhe Road, Shanghai 200437, China. Electronic address: drlifulun@shutcm.edu.cn. FAU - Deng, Yu AU - Deng Y AD - Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu 610106, China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu 610106, China; School of Basic Medical Sciences, Chengdu University, NO. 2025, Chengluo Road, Chengdu 610106, China. Electronic address: dengyu@cdu.edu.cn. LA - eng PT - Journal Article DEP - 20220928 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - 0 (Interleukin-33) RN - 207137-56-2 (Interleukin-4) RN - 2543-94-4 (phellopterin) RN - 0 (STAT3 Transcription Factor) RN - 0 (Cytokines) RN - 37341-29-0 (Immunoglobulin E) RN - 3K9958V90M (Ethanol) RN - 0 (STAT3 protein, human) SB - IM MH - Humans MH - *Dermatitis, Atopic MH - Interleukin-33/metabolism MH - Interleukin-4/metabolism MH - STAT3 Transcription Factor/metabolism MH - Keratinocytes MH - Cytokines/metabolism MH - Inflammation/metabolism MH - Immunoglobulin E/metabolism MH - Ethanol/metabolism OTO - NOTNLM OT - Atopic dermatitis OT - IL-33 OT - Phellopterin OT - STAT3 activation OT - TSLP COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/10/01 06:00 MHDA- 2022/10/21 06:00 CRDT- 2022/09/30 18:16 PHST- 2022/07/15 00:00 [received] PHST- 2022/09/15 00:00 [revised] PHST- 2022/09/20 00:00 [accepted] PHST- 2022/10/01 06:00 [pubmed] PHST- 2022/10/21 06:00 [medline] PHST- 2022/09/30 18:16 [entrez] AID - S1567-5769(22)00754-8 [pii] AID - 10.1016/j.intimp.2022.109270 [doi] PST - ppublish SO - Int Immunopharmacol. 2022 Nov;112:109270. doi: 10.1016/j.intimp.2022.109270. Epub 2022 Sep 28.