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HMGB1 Enhances the Proinflammatory Activity of Lipopolysaccharide by Promoting the Phosphorylation of MAPK p38 through Receptor for Advanced Glycation End Products¹

Yang-Hua Qin,^2* Sheng-Ming Dai,² Gu-Sheng Tang,^* Jun Zhang,^* Ding Ren,^* Zhi-Wei Wang, and Qian Shen^3*

^*Department of Laboratory Diagnosis, Department of Rheumatology and Immunology, and Department of Orthopedics, Changhai Hospital, Second Military Medical University, Shanghai, Peoples Republic of China

High mobility group box-1 (HMGB1) protein was originally characterized as a nuclear DNA-binding protein, and was described to have an extracellular role when involved in cellular activation and proinflammatory responses. In the present study, we have found that the proinflammatory activity of recombinant HMGB1 proteins is determined by the containing endotoxin level, and HMGB1 that contains few endotoxins fails to stimulate macrophages to secrete proinflammatory cytokines. HMGB1 acts as a ligand of receptor for advanced glycation end products (RAGE) and works in synergy with LPS in activating the macrophages in vitro. In vivo, intra-articular injections of HMGB1 act in synergy with LPS to induce experimental arthritis in mice. HMGB1 promotes the phosphorylation of MAPK p38 and the activation of NF-B through RAGE, and then enhances the expression of proinflammatory cytokines. These results demonstrate that HMGB1 enhances the proinflammatory activity of LPS by promoting the phosphorylation of MAPK p38 and by the activation of NF-B through RAGE.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant 30872338 from the National Natural Science Foundation of China and by Grant 2002AA214090 from the National High Biotechnology Development Program of China.

² Y.H.Q. and S.M.D. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Qian Shen, Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, People’s Republic of China. E-mail address: msminli{at}hotmail.com

⁴ Abbreviations used in this paper: HMGB1, high mobility group box 1; RAGE, receptor for advanced glycation end products.

⁵ The online version of this article contains supplementary material.