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1、IF: 5.745 (2010),Key Words：,ST2 TLR2 signaling BLP and BLP-induced tolerance,SEPSIS SYNDROME AND SEPTIC SHOCK,MAJOR CAUSES OF MORBIDITY AND MORTALITY IN HOSPITALISED PATIENTS MORTALITY AT 40% IN THE UNITED STATES AND EUROPE,SIRS,ARDS,BLP (Bacterial Lipoprotein) Tolerance,LETHAL BLP or LPS,SUB-LETHAL
2、 BLP,HIGH MORTALITY (80%),REDUCED MORTALITY,LETHAL BLP 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 p
3、roinflammatory cytokines than do 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 Immun
4、ol. 2003; 170:14-18) Induction of bacterial 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 form
5、ation (J. Leuko. Biol. 2006; 79: 867-875),Background,AIMS,To clarify whether ST2 negatively regulates TLR2 signaling To 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 BL
6、P-stimulated NF-B activation in HEK293-TLR2 cells,Overexpression 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 stimulation Overexpression of
7、 ST2 attenuates BLP-induced NF-B activation Overexpression 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
8、 show moderate but significantly attenuated TNF release in 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
9、 expression MyD88/IRAK1 complex,Flow chart of ST2 on BLP-induced tolerance,Isolation,BMMs,TLR2 MyD88 IRAK1,0, 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
10、,association,TLR2& MyD88 MyD88&IRAK1,Part 2: To examine whether ST2 is 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,MyD8
11、8/IRAK1 immuno-complex formation in naive and BLP-tolerised wild-type and 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 ob
12、served 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,