DOK3 Negatively Regulates LPS Responses and Endotoxin Tolerance 英文参考文献.docVIP

DOK3NegativelyRegulatesLPSResponsesand EndotoxinTolerance QishengPeng1,2,JasonL.O’Loughlin1,MaryBethHumphrey1,3* 1DepartmentofMedicine,UniversityofOklahomaHealthSciencesCenter,OklahomaCity,Oklahoma,UnitedStatesofAmerica,2KeyLaboratoryforZoonosisResearch, MinistryofEducation,JilinUniversity,Changchun,China,3DepartmentofVeteransAffairs,OklahomaCity,Oklahoma,UnitedStatesofAmerica Abstract Innate immune activation via Toll-like receptors (TLRs), although critical for host defense against infection, must be regulated to prevent sustained cell activation that can lead to cell death. Cells repeatedly stimulated with lipopolysaccharide (LPS) develop endotoxin tolerance making the cells hypo-responsive to additional TLR stimulation. We show here that DOK3 is a negative regulator of TLR signaling by limiting LPS-induced ERK activation and cytokine responses in macrophages. LPS induces ubiquitin-mediated degradation of DOK3 leading to SOS1 degradation and inhibitionofERKactivation.DOK3micearehypersensitivetosublethaldosesofLPSandhavealteredcytokineresponsesin vivo. During endotoxin tolerance, DOK3 expression remains stable, and it negatively regulates the expression of SHIP1, IRAK-M, SOCS1,andSOS1.As such, DOK3-deficient macrophagesaremoresensitive toLPS-induced tolerancebecoming tolerant at lower levels of LPS than wild type cells. Taken together, the absence of DOK3 increases LPS signaling, contributingtoLPS-inducedtolerance.Thus,DOK3playsaroleinTLRsignalingduringbothna?¨veandendotoxin-induced tolerantconditions. Citation:PengQ,O’LoughlinJL,HumphreyMB(2012)DOK3NegativelyRegulatesLPSResponsesandEndotoxinTolerance.PLoSONE7(6):e39967.doi:10.1371/ journal.pone.0039967 Editor:StefanBereswill,Charite′-University MedicineBerlin,Germany ReceivedMarch6,2012;AcceptedJune5,2012;PublishedJune27,2012 Thisisanopen-accessarticle,freeofallcopyright,andmaybefreelyreproduced,distributed,transmitted,modified,builtupon,orotherwiseusedbyanyonefor anylawfulpurpose.Theworkismadeavailableu