高级病生第5次——Regulatory effect of ST2.pptVIP

* * * * * * * * * * * * 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 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 proinflammatory 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 Immunol. 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 formation (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 Part 1: To clarify whether ST2 negatively regulates TLR2 signaling Part 1: To clarify whether ST2 negatively regulates TLR2 signaling Overexpression of ST2 attenuates BLP-stimulated NF-?B activation in HEK293-TLR2 cells Unstimulated BLP 0 5 10 15 20 25 0 50 75 100 ng hST2 (ng) Fold of stimulation Overexpression of ST2 inhibits MyD88-induced NF-?B activation 0 50 100 150 EV 50 75 100 MyD88 (25ng) Fold of stimulation hST2 (ng) Part 1: To clarify whether ST2 negatively regulates