The Journal of Experimental Medicine
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Published online 21 August 2000.
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© The Rockefeller University Press, 0022-1007/2000/8/565/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 4, August 21, 2000 565-570

Brief Definitive Report

High Mobility Group 1 Protein (HMG-1) Stimulates Proinflammatory Cytokine Synthesis in Human Monocytes

Ulf Anderssona,b, Haichao Wangd, Karin Palmblada,b, Ann-Charlotte Avebergera,b, Ona Bloomc, Helena Erlandsson-Harrisa, Alfred Jansona,b, Riikka Kokkolaa, Minghuang Zhangd, Huan Yangd, and Kevin J. Traceyd
a Department of Medicine, Rheumatology Unit, Karolinska Hospital, 17176 Stockholm, Sweden
b Department of Rheumatology, Astrid Lindgren's Children's Hospital, Karolinska Institutet, 17176 Stockholm, Sweden
c Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021
d Laboratory of Biomedical Science, North Shore University Hospital, New York University School of Medicine, Manhasset, New York 11030

Correspondence to: Ulf Andersson, Department of Rheumatology, Astrid Lindgren's Children's Hospital, 17176 Stockholm, Sweden. Tel:46-8-51775684 Fax:46-8-7175701 E-mail:ulf{at}mbox313.swipnet.se.

Lipopolysaccharide (LPS) is lethal to animals because it activates cytokine release, causing septic shock and tissue injury. Early proinflammatory cytokines (e.g., tumor necrosis factor [TNF] and interleukin [IL]-1) released within the first few hours of endotoxemia stimulate mediator cascades that persist for days and can lead to death. High mobility group 1 protein (HMG-1), a ubiquitous DNA-binding protein, was recently identified as a "late" mediator of endotoxin lethality. Anti–HMG-1 antibodies neutralized the delayed increase in serum HMG-1, and protected against endotoxin lethality, even when passive immunization was delayed until after the early cytokine response. Here we examined whether HMG-1 might stimulate cytokine synthesis in human peripheral blood mononuclear cell cultures. Addition of purified recombinant HMG-1 to human monocyte cultures significantly stimulated the release of TNF, IL-1{alpha}, IL-1ß, IL-1RA, IL-6, IL-8, macrophage inflammatory protein (MIP)-1{alpha}, and MIP-1ß; but not IL-10 or IL-12. HMG-1 concentrations that activated monocytes were within the pathological range previously observed in endotoxemic animals, and in serum obtained from septic patients. HMG-1 failed to stimulate cytokine release in lymphocytes, indicating that cellular stimulation was specific. Cytokine release after HMG-1 stimulation was delayed and biphasic compared with LPS stimulation. Computer-assisted image analysis demonstrated that peak intensity of HMG-1–induced cellular TNF staining was comparable to that observed after maximal stimulation with LPS. Administration of HMG-1 to Balb/c mice significantly increased serum TNF levels in vivo. Together, these results indicate that, like other cytokine mediators of endotoxin lethality (e.g., TNF and IL-1), extracellular HMG-1 is a regulator of monocyte proinflammatory cytokine synthesis.

Key Words: HMG-1, tumor necrosis factor, monocyte activation, septic shock, lipopolysaccharide


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