A major ingredient of green tea rescues mice from lethal sepsis partly by inhibiting HMGB1.
BACKGROUND
The pathogenesis of sepsis is mediated in part by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., TNF, IL-1, and IFN-gamma) and late (e.g., HMGB1) pro-inflammatory cytokines. Our recent discovery of HMGB1 as a late mediator of lethal sepsis has prompted investigation for development of new experimental therapeutics. We previously reported that green tea brewed from the leaves of the plant Camellia sinensis is effective in inhibiting endotoxin-induced HMGB1 release.


RESULTS
Here we demonstrate that its major component, (-)-epigallocatechin-3-gallate (EGCG), but not catechin or ethyl gallate, dose-dependently abrogated HMGB1 release in macrophage/monocyte cultures, even when given 2-6 hours post LPS stimulation. Intraperitoneal administration of EGCG protected mice against lethal endotoxemia, and rescued mice from lethal sepsis even when the first dose was given 24 hours after cecal ligation and puncture. The therapeutic effects were partly attributable to: 1) attenuation of systemic accumulation of proinflammatory mediator (e.g., HMGB1) and surrogate marker (e.g., IL-6 and KC) of lethal sepsis; and 2) suppression of HMGB1-mediated inflammatory responses by preventing clustering of exogenous HMGB1 on macrophage cell surface.


CONCLUSIONS
Taken together, these data suggest a novel mechanism by which the major green tea component, EGCG, protects against lethal endotoxemia and sepsis.
Li
Wei
W
Department of Emergency Medicine, North Shore University Hospital-New York University School of Medicine, Manhasset, New York, United States of America.
Ashok
Mala
M
Li
Jianhua
J
Yang
Huan
H
Sama
Andrew E
AE
Wang
Haichao
H
D000818:Animals; D002392:Catechin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy*; D013662:Tea / Q000737:chemistry*
D024243:HMGB1 Protein; D011994:Recombinant Proteins; D013662:Tea; D009569:Nitric Oxide; D002392:Catechin; C045651:epigallocatechin gallate