Yongyu Mei1, Chen Fang1, Shaozhen Ding1, Xiaochang Liu1, Jing Hu1, Jianming Xu1, Qiao Mei2. 1. Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, The Key Laboratory of Digestive Diseases of Anhui Province, Hefei, China. 2. Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, The Key Laboratory of Digestive Diseases of Anhui Province, Hefei, China. Electronic address: meiqiao@hotmail.com.
Abstract
BACKGROUND: Macrophages are a primary type of innate immune cells activated in colitis. Kv1.3 channel is one of the major potassium channels in macrophages. NLRP3 inflammasome is a downstream molecule of Kv1.3 channel. PAP-1, a specific Kv1.3 channel blocker, has been shown to have immune-regulatory effects. OBJECTIVE: To investigate the effect of PAP-1 on intestinal inflammation in DSS-induced colitis and explore its possible mechanism. METHODS: C57BL/6 mice were divided into four groups: normal control group, normal+PAP-1 injection group, DSS model group, DSS model+PAP-1 injection group. Experimental colitis was induced by 5% DSS treatment; mice were injected intraperitoneally with PAP-1 from the first day for 7 consecutive days; then all mice were sacrificed, followed by isolation of colon tissue, peritoneal macrophages and spleen macrophages. The anti-inflammatory effects of PAP-1 and the expression levels of Kv1.3, iNOS, pro-IL-1β, IL-1β and NLRP3 inflammasome were measured. RESULTS: PAP-1 reduced DSS-induced colonic pathological damage, DAI score, MPO activity and levels of IL-1, IL-6, TNF-a, IL-18. Compared with the DSS model group, the expression of Kv1.3, iNOS, NLRP3, ASC, caspase-1p20, pro-IL-1β and IL-1β in colon were decreased in the DSS-induced colitis mice with PAP-1 injection. PAP-1 also reduced the expression of Kv1.3, iNOS, NLRP3, caspase-1p20 and IL-1β on macrophages in colitis mice. CONCLUSION: PAP-1 had protective effects on DSS-induced colitis, which might be ascribed to the regulation of NLRP3 inflammasome pathway. Therefore, we found that PAP-1 was useful as a therapeutic agent in IBD and suggested a potential important role of PAP-1 in NLRP3 inflammasome-associated diseases.
BACKGROUND: Macrophages are a primary type of innate immune cells activated in colitis. Kv1.3 channel is one of the major potassium channels in macrophages. NLRP3 inflammasome is a downstream molecule of Kv1.3 channel. PAP-1, a specific Kv1.3 channel blocker, has been shown to have immune-regulatory effects. OBJECTIVE: To investigate the effect of PAP-1 on intestinal inflammation in DSS-induced colitis and explore its possible mechanism. METHODS: C57BL/6 mice were divided into four groups: normal control group, normal+PAP-1 injection group, DSS model group, DSS model+PAP-1 injection group. Experimental colitis was induced by 5% DSS treatment; mice were injected intraperitoneally with PAP-1 from the first day for 7 consecutive days; then all mice were sacrificed, followed by isolation of colon tissue, peritoneal macrophages and spleen macrophages. The anti-inflammatory effects of PAP-1 and the expression levels of Kv1.3, iNOS, pro-IL-1β, IL-1β and NLRP3 inflammasome were measured. RESULTS:PAP-1 reduced DSS-induced colonic pathological damage, DAI score, MPO activity and levels of IL-1, IL-6, TNF-a, IL-18. Compared with the DSS model group, the expression of Kv1.3, iNOS, NLRP3, ASC, caspase-1p20, pro-IL-1β and IL-1β in colon were decreased in the DSS-induced colitismice with PAP-1 injection. PAP-1 also reduced the expression of Kv1.3, iNOS, NLRP3, caspase-1p20 and IL-1β on macrophages in colitismice. CONCLUSION:PAP-1 had protective effects on DSS-induced colitis, which might be ascribed to the regulation of NLRP3 inflammasome pathway. Therefore, we found that PAP-1 was useful as a therapeutic agent in IBD and suggested a potential important role of PAP-1 in NLRP3 inflammasome-associated diseases.