Journal ArticleDOI
HMG-1 as a Late Mediator of Endotoxin Lethality in Mice
Haichao Wang,Ona Bloom,Minghuang Zhang,Jaideep M. Vishnubhakat,Michael Ombrellino,Jiantu Che,Asia Frazier,Huan Yang,Svetlana Ivanova,Lyudmila V. Borovikova,Kirk R. Manogue,Eugen Faist,Edward Abraham,Jan Andersson,Ulf Andersson,Patricia E. Molina,Naji N. Abumrad,Andrew E. Sama,Kevin J. Tracey +18 more
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TLDR
High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1, and showed increased serum levels after endotoxin exposure, suggesting that this protein warrants investigation as a therapeutic target.Abstract:
Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.read more
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Increased serum HMGB1 level is associated with coronary artery disease in nondiabetic and type 2 diabetic patients
Xiao Xiang Yan,Lin Lu,Wen Hui Peng,Ling Jie Wang,Qi Zhang,Rui Yan Zhang,Qiu Jing Chen,Weifeng Shen +7 more
TL;DR: It is demonstrated that increased serum HMGB1 level is associated with CAD in nondiabetic and type 2 diabetic patients, so did other major conventional risk factors.
Journal ArticleDOI
Receptor for advanced glycation end products (RAGE) in a dash to the rescue: inflammatory signals gone awry in the primal response to stress.
Kevan C. Herold,Bernhard Moser,Yali Chen,Shan Zeng,Shi Fang Yan,Ravichandran Ramasamy,Jean C. Emond,Raphael Clynes,Ann Marie Schmidt +8 more
TL;DR: The concept that the ligands of RAGE comprise a primal program in the acute response to stress is suggested, which suggests that the function of these ligand families may be transformed from ones linked to rapid repair to those that drive chronic disease.
Journal ArticleDOI
β2-Adrenoreceptors of regulatory lymphocytes are essential for vagal neuromodulation of the innate immune system.
Gergely Vida,Geber Peña,Alexandre Kanashiro,Maria del Rocio Thompson-Bonilla,David Palange,Edwin A. Deitch,Luis Ulloa +6 more
TL;DR: Results indicate that β2‐adrenoceptors in regulatory lymphocytes are critical for the anti‐inflammatory potential of the parasympathetic vagus nerve, and they represent a potential pharmacological target for sepsis.
Journal ArticleDOI
The expression of HMGB1 protein and its receptor RAGE in human malignant tumors.
TL;DR: The expression of HMGB1 protein in malignant human tumors of different differentiation level and in tumor metastasis is studied and it is found that in metastatic cells, RAGE exhibits higher level of expression losing its specific granular cytosolic pattern characteristic for the primary tumors.
Journal ArticleDOI
Toll-Like Receptor 4 Has an Essential Role in Early Skin Wound Healing
TL;DR: The results suggest that inflammatory cytokine production by injured NHEK is stimulated via the TLR4-p38 and JNK MAPK signaling pathway, and provide evidence for a role ofTLR4 at sites of injury, and suggest that TLR 4 is an important regulator of wound inflammation.
References
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Journal ArticleDOI
Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene
Alexander Poltorak,Xiaolong He,Irina Smirnova,Mu Ya Liu,Christophe Van Huffel,Xin Du,Dale Birdwell,E. Alejos,M. Silva,Chris Galanos,Marina Freudenberg,Paola Ricciardi-Castagnoli,Betsy Layton,Bruce Beutler +13 more
TL;DR: The mammalian Tlr4 protein has been adapted primarily to subserve the recognition of LPS and presumably transduces the LPS signal across the plasma membrane.
Journal Article
Defective LPS signaling in C3 H/HeJ and C57 BL/10 ScCr mice: Mutations in Tlr4 Gene
Alexander Poltorak,Xiaolong He,Irina Smirnova,Mu Ya Liu,C. Van Huffel,Xin Du,Dale Birdwell,E. Alejos,M. Suva,Chris Galanos,Marina Freudenberg,Paola Ricciardi-Castagnoli,B. Layton,Bruce Beutler +13 more
Journal ArticleDOI
Shock and tissue injury induced by recombinant human cachectin.
Kevin J. Tracey,Bruce Beutler,Stephen F. Lowry,James P Merryweather,Stephen D. Wolpe,Ian W. Milsark,Robert J. Hariri,Thomas J. Fahey,Alejandro Zentella,J. D. Albert,G. Tom Shires,Anthony Cerami +11 more
TL;DR: It appears that a single protein mediator (cachectin) is capable of inducing many of the deleterious effects of endotoxin.
Journal ArticleDOI
Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia
Kevin J. Tracey,Kevin J. Tracey,Yuman Fong,David G. Hesse,Kirk R. Manogue,Annette T. Lee,George C. Kuo,Stephen F. Lowry,Anthony Cerami +8 more
TL;DR: Protection against shock, vital organ dysfunction, persistent stress hormone release and death was conferred by administration of antibodies 2 h before bacterial infusion, indicating that cachectin is a mediator of fatal bacteraemic shock and suggesting that antibodies against Cachectin offer a potential therapy of life-threatening infection.
Journal ArticleDOI
Detection of circulating tumor necrosis factor after endotoxin administration.
Hamish R. Michie,Kirk R. Manogue,David R. Spriggs,Arthur Revhaug,S. T. O'Dwyer,Charles A. Dinarello,Anthony Cerami,Sheldon M. Wolff,Douglas W. Wilmore +8 more
TL;DR: It is concluded that the response to endotoxin is associated with a brief pulse of circulating tumor necrosis factor and that the resultant responses are effected through the cyclooxygenase pathway.