首页 | 本学科首页   官方微博 | 高级检索  
     


Cytolethal distending toxin‐induced release of interleukin‐1β by human macrophages is dependent upon activation of glycogen synthase kinase 3β, spleen tyrosine kinase (Syk) and the noncanonical inflammasome
Authors:Bruce J. Shenker  Lisa M. Walker  Zeyed Zekavat  David M. Ojcius  Pei‐Rong Huang  Kathleen Boesze‐Battaglia
Abstract:
Cytolethal distending toxins (Cdt) are a family of toxins produced by several human pathogens which infect mucocutaneous tissue and induce inflammatory disease. We have previously demonstrated that the Aggregatibacter actinomycetemcomitans Cdt induces a pro‐inflammatory response from human macrophages which involves activation of the NLRP3 inflammasome. We now demonstrate that in addition to activating caspase‐1 (canonical inflammasome), Cdt treatment leads to caspase‐4 activation and involvement of the noncanonical inflammasome. Cdt‐treated cells exhibit pyroptosis characterised by cleavage of gasdermin‐D (GSDMD), release of HMGB1 at 24 hr and LDH at 48 hr. Inhibition of either the canonical (caspase‐1) or noncanonical (caspase‐4) inflammasome blocks both Cdt‐induced release of IL‐1β and induction of pyroptosis. Analysis of upstream events indicates that Cdt induces Syk phosphorylation (activation); furthermore, blockade of Syk expression and inhibition of pSyk activity inhibit both Cdt‐induced cytokine release and pyroptosis. Finally, we demonstrate that increases in pSyk are dependent upon Cdt‐induced activation of GSK3β. These studies advance our understanding of Cdt function and provide new insight into the virulence potential of Cdt in mediating the pathogenesis of disease caused by Cdt‐producing organisms such as A. actinomycetemcomitans.
Keywords:   Aggregatibacter actinomycetemcomitans  inflammasome  mechanism of action  microbial–  cell interaction  toxins
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号