期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2013
卷号：110
期号：21
页码：8656-8661
DOI：10.1073/pnas.1221652110
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Deregulated Toll-like receptor (TLR)-triggered inflammatory responses that depend on NF-{kappa}B are detrimental to the host via excessive production of proinflammatory cytokines, including TNF-. Stat2 is a critical component of type I IFN signaling, but it is not thought to participate in TLR signaling. Our study shows that LPS-induced lethality in Stat2-/- mice is accelerated as a result of increased cellular transmigration. Blocking intercellular adhesion molecule-1 prevents cellular egress and confers survival of Stat2-/- mice. The main determinant of cellular egress in Stat2-/- mice is the genotype of the host and not the circulating leukocyte. Surprisingly, lethality and cellular egress observed on Stat2-/- mice are not associated with excessive increases in classical sepsis cytokines or chemokines. Indeed, in the absence of Stat2, cytokine production in response to multiple TLR agonists is reduced. We find that Stat2 loss leads to reduced expression of NF-{kappa}B target genes by affecting nuclear translocation of NF-{kappa}B. Thus, our data reveal the existence of a different mechanism of LPS-induced lethality that is independent of NF-{kappa}B triggered cytokine storm but dependent on cellular egress.
