title: Fluorofenidone inhibits macrophage IL-1β production by suppressing inflammasome activity.
abstract: Interleukin-1 beta (IL-1β) is a potent pro-inflammatory and pro-fibrotic cytokine that plays an important role in renal fibrosis. Fluorofenidone (AKF-PD) is a novel pyridone agent that exerts a strong renal anti-fibrotic effect. We previously found that administration of AKF-PD could significantly attenuate IL-1β production in vitro and in vivo. However, the underlying mechanism is not fully understood. Here we show that AKF-PD has no effect on the expression of pro-IL-1β in activated mouse macrophages in vitro. Instead, AKF-PD inhibits the inflammasome, lowering caspase-1 levels and thereby decreasing cleavage of pro-IL-1β into IL-1β. AKF-PD was found to block inflammasome activity induced by various signals, including ATP, alum crystals, and Salmonella typhimurium. These results provide a novel mechanistic insight into how AKF-PD exerts its anti-inflammatory and anti-fibrotic activities, and suggest that AKF-PD might block IL-1β production via suppression of inflammasomes in renal fibrosis. In addition, the results suggest that AKF-PD may be of therapeutic potential in other inflammasome-related diseases.
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Nephrology, The First Affiliated of Liaoning Medical University, Jinzhou, Liaoning 121001, China.
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Zhangzhe
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Mei
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Xiangning
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Respiratory, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Meng
authors.affiliation: Department of Hematology, The Third Xiangya Hospital, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Ben
authors.initials: B
authors.lastname: Lv
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Jishi
authors.initials: J
authors.lastname: Liu
authors.affiliation: Faculty of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410008, China.
authors.forename: Gaoyun
authors.initials: G
authors.lastname: Hu
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; State Key Laboratory of Medical Genetics of China, Central South University, Changsha, Hunan 410008, China. Electronic address: taolj@csu.edu.cn.
authors.forename: Lijian
authors.initials: L
authors.lastname: Tao
mesh_terms: D000255:Adenosine Triphosphate / Q000276:immunology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000942:Antigens, Bacterial / Q000276:immunology; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007165:Immunosuppression Therapy; D058847:Inflammasomes / Q000187:drug effects* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009395:Nephritis, Interstitial / Q000188:drug therapy* / Q000276:immunology; D059748:Proteolysis / Q000187:drug effects; D011728:Pyridones / Q000494:pharmacology*; D012486:Salmonella typhimurium / Q000276:immunology*
chemical_list: C511655:5-methyl-1-(3-fluorophenyl)-2-(1H)-pyridone; D000893:Anti-Inflammatory Agents; D000942:Antigens, Bacterial; D058847:Inflammasomes; D053583:Interleukin-1beta; D011728:Pyridones; D000255:Adenosine Triphosphate; D020170:Caspase 1
keywords: Fluorofenidone; IL-1β; Inflammasome