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1、IF:5.745(2010),Key Words：,ST2TLR2 signalingBLP and BLP-induced tolerance,SEPSIS SYNDROME AND SEPTIC SHOCK,MAJOR CAUSES OFMORBIDITY AND MORTALITY IN HOSPITALISED PATIENTSMORTALITY AT 40%IN THE UNITED STATES AND EUROPE,SIRS,ARDS,BLP(Bacterial Lipoprotein)Tolerance,LETHALBLP or LPS,SUB-LETHALBLP,HIGH M
2、ORTALITY(80%),REDUCEDMORTALITY,LETHALBLP or LPS,TNF-a,TNF-a,SIRS,TOLERANCE,1.Wang JH,et al.J.Immunol.2003;170:14-18.2.Buckley JM,et al.J.Leukoc.Biol.2006;80:731-741.,ST2 Function,Background,Nat.Immunol,2004;5:373-379,Macrophages from ST2-deficient mice produce more proinflammatory cytokines than do
3、cells from wild-type mice.ST2 is required for endotoxin tolerance,Background,ST2 belongs to TIR(Toll-IL-1R)domain-containing superfamily members,Our Previous work:,Cutting edge:Bacterial lipoprotein induces endotoxin-independent tolerance to septic shock(J Immunol.2003;170:14-18)Induction of bacteri
4、al lipoprotein tolerance is associated with suppression of TLR2 expression(J.Biol.Chem.2002;277:36068-36075)Bacterial lipoprotein-induced self-tolerance and cross-tolerance to LPS are associated with reduced IRAK-1 expression and MyD88-IRAK complex formation(J.Leuko.Biol.2006;79:867-875),Background,
5、AIMS,To clarify whether ST2 negatively regulates TLR2 signalingTo examine whether ST2 is a key molecule for inducing BLP tolerance,Enhanced TNF production is observed in BLP-stimulated ST2-deficient macrophages,Overexpression of ST2 attenuates BLP-stimulated NF-B activation in HEK293-TLR2 cells,Over
6、expression of ST2 inhibits MyD88-induced NF-B activation,Effect of ST2 overexpression on IRAK1-induced NF-B activation,Fold of stimulation,Summary of part I,Increased TNF release in ST2-deficient macrophages upon BLP stimulationOverexpression of ST2 attenuates BLP-induced NF-B activation Overexpress
7、ion of ST2 inhibites MyD88 induced NF-B activation Overexpression of ST2 did not affect IRAK1 mediated NF-B activation,ST2 exerts its negative regulatory function on TLR2 signaling pathway through MyD88,BLP pretreated ST2-deficient macrophages show moderate but significantly attenuated TNF release i
8、n response to a second BLP stimulation,Part 2:To examine whether ST2 is a key molecule for inducing BLP tolerance,Expression levels of these signal molecules and their immuno-complex formations are very important for signal transduction,IRAK1 expression MyD88/IRAK1 complex,Flow chart of ST2 on BLP-i
9、nduced tolerance,Isolation,BMMs,TLR2MyD88IRAK1,0,10,20,30 min,BLP 100 ng/ml,24 h,Untreated,BMMs(Bone marrow-derived macrophages),expression,BLP 1000 ng/ml,Non tolerant BMM,BLP tolerant BMM,Co-IP/WB analysis,ST2 KO mice,Wild type mice,association,TLR2&MyD88MyD88&IRAK1,Part 2:To examine whether ST2 is
10、 a key molecule for inducing BLP tolerance,Project:To examine whether ST2 is a key molecule for inducing BLP tolerance,Expression of IRAK1 in naive and BLP-tolerised wild-type and ST2-deficient BMM cells upon BLP stimulation,MyD88/IRAK1 immuno-complex formation in naive and BLP-tolerised wild-type a
11、nd ST2-deficient BMM cells upon BLP stimulation,Project:To examine whether ST2 is a key molecule for inducing BLP tolerance,In response to a second BLP stimulation,a moderate but significantly attenuated TNF-a production was observed in BLP-pretreated ST2-deficient BMM.MyD88-IRAK complex formation was down-regulated in BLP-pretreated ST2-deficient BMM,indicating BLP tolerance develops independent of ST2,Summary of part II,Conclusion,ST2 acts as a negative regulator in TLR2 signalling ST2 is not responsible for BLP-induced tolerance,THANKS,
