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

doi:10.1111/bph.14667

	Inhibition of phosphodiesterase-4 attenuates murine ulcerative colitis through interference with mucosal immunity
	Li, Heng 1,2; Fan, Chen 1; Feng, Chunlan 1; Wu, Yanwei 1; Lu, Huimin 1,2; He, Peilan 3; Yang, Xiaoqian 3; Zhu, Fenghua 3; Qi, Qing 1; Gao, Yuanzhuo 1,2
刊名	BRITISH JOURNAL OF PHARMACOLOGY
	2019-07-01
卷号	176 期号:13 页码:2209-2226
ISSN号	0007-1188
DOI	10.1111/bph.14667
通讯作者	Zuo, Jianping(jpzuo@simm.ac.cn) ; Tang, Wei(tangwei@simm.ac.cn)
英文摘要	Background and Purpose Ulcerative colitis (UC) is an aetiologically refractory inflammatory disease, accompanied by dysfunction of the epithelial barrier and intestinal inflammation. Phosphodiesterase-4 (PDE4) serves as an intracellular proinflammatory enzyme, hydrolyzing and inactivating cAMP. Though PDE4 inhibitors have been approved for pulmonary and dermatological diseases, the role of PDE4 inhibition in modulating mucosal immunity in the intestine remains ill-defined. This study was designed to explore whether PDE4 inhibition by apremilast exerts protective effects in dextran sulfate sodium-induced murine UC. Experimental Approach Intestinal inflammation and disease severity were evaluated by morphological, histopathological and biochemical assays, and in vivo imaging. Expression of inflammatory mediators, components of PDE4-mediated pathways in colon and macrophages were determined using quantitative real-time PCR, ELISA, Luminex assay, immunostaining, or western blotting, along with siRNA knockdown. Immune cells in mesenteric lymph nodes and colonic lamina propria were analysed by flow cytometry. Key Results Apremilast attenuated clinical features of UC, suppressing microscopic colon damage, production of inflammatory mediators, oxidative stresses, and fibrosis. Apremilast also promoted epithelial barrier function and inhibited infiltration of immune cells into inflamed tissues, through decreasing expression of chemokines and chemokine receptors. Furthermore, in UC, PDE4A, PDE4B, and PDE4D were highly expressed in colon. Apremilast not only inhibited PDE4 isoform expression but also activated PKA-CREB and Epac-Rap1 pathways and subsequently suppressed MAPK, NF-kappa B, PI3K-mTOR, and JAK-STAT-SOCS3 activation. Conclusion and Implications Inhibition of PDE4 by apremilast protected against UC, by interfering with mucosal immunity. These findings represent a promising strategy for regulating intestinal inflammation.
资助项目	Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020231] ; National Science and Technology Major Project Key New Drug Creation and Manufacturing Program[2018ZX09711002-006-011]
WOS关键词	INFLAMMATORY-BOWEL-DISEASE ; CONCISE GUIDE ; EXPERIMENTAL-DESIGN ; EPITHELIAL BARRIER ; MECHANISMS ; APREMILAST ; CELLS ; PATHOGENESIS ; PUBLICATION ; CHEMOKINES
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	WILEY
WOS记录号	WOS:000470913600007
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/289658]
专题	中国科学院上海药物研究所
通讯作者	Zuo, Jianping; Tang, Wei
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Antiinflammat, Shanghai, Peoples R China 2.Univ Chinese Acad Sci, Sch Pharm, Beijing, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Lab Immunopharmacol, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Li, Heng,Fan, Chen,Feng, Chunlan,et al. Inhibition of phosphodiesterase-4 attenuates murine ulcerative colitis through interference with mucosal immunity[J]. BRITISH JOURNAL OF PHARMACOLOGY,2019,176(13):2209-2226.
APA	Li, Heng.,Fan, Chen.,Feng, Chunlan.,Wu, Yanwei.,Lu, Huimin.,...&Tang, Wei.(2019).Inhibition of phosphodiesterase-4 attenuates murine ulcerative colitis through interference with mucosal immunity.BRITISH JOURNAL OF PHARMACOLOGY,176(13),2209-2226.
MLA	Li, Heng,et al."Inhibition of phosphodiesterase-4 attenuates murine ulcerative colitis through interference with mucosal immunity".BRITISH JOURNAL OF PHARMACOLOGY 176.13(2019):2209-2226.