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

By U. Andersson, Haichao Wang, K. Palmblad, A. Aveberger, O. Bloom, H. Erlandsson‐Harris, A. Janson, R. Kokkola, Minghuang Zhang, Huan Yang and 1 more. Journal of Experimental Medicine, 2000

1,487 citations recorded by the source corpus.

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-1α, IL-1β, IL-1RA, IL-6, IL-8, macrophage inflammatory protein (MIP)-1α, and MIP-1β; 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.

Subfields: Clinical Biochemistry, Immunology, Nutrition and Dietetics

View Paper: https://www.semanticscholar.org/paper/2af1979a4f085e4e782e2d303ef35cc16d4c58d0

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Clinical Biochemistry

1. Kevin J. Tracey
2. H. Kono
3. K. Rock
4. U. Andersson
5. A. Manfredi
6. M. Bianchi
7. Timothy R. Billiar
8. A. Tsung

In Immunology

1. Kevin J. Tracey
2. H. Kono
3. K. Rock
4. E. Latz
5. M. Bianchi
6. U. Andersson
7. A. Manfredi
8. Peter Vandenabeele

In Nutrition and Dietetics

1. Douglas R. Green
2. Kevin J. Tracey
3. H. Kono
4. K. Rock
5. A. Manfredi
6. D. Sohn
7. Jong Seong Roh
8. Beth Levine

Citations in the corpus

• IMMUNE TOLERANCE INDUCTION BY APOPTOTIC CELLS REQUIRES CASPASE-DEPENDENT OXIDATION OF HMGB1 (2008, background): “These include uric acid (Shi et al., 2003), calreticulin (Obeid et al., 2007a; Obeid et al., 2007b), HSP70 (Millar et al., 2003), and HMGB1 (Andersson et al., 2000; Messmer et al., 2004).”
• High‐mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity (2007, background): “Loss of HMGB1 leads to a defect in the response to CpG DNA in terms of IL-6, IL-12, TNF-a, and inducible nitric-oxide synthase expression.”
• How dying cells alert the immune system to danger (2008, background): “HMGB1 released from necrotic cells was shown to stimulate monocytes in vitro to produce pro-inflammatory mediator”
• Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation (2002, background): “Thus, there is significant potential for developing cholinergic agonists that target α7 subunits on peripheral immune cells for use as anti-inflammatory agents to inhibit release of TNF and other proinflammatory cytokines (for example, high mobility group box-1 protein”
• HMGB1 SIGNALS THROUGH TOLL-LIKE RECEPTOR (TLR) 4 AND TLR2 (2006, background): “Bank (New York Blood Center, Melville, NY) (24).”
• Immunogenic cell death and DAMPs in cancer therapy (2012, background): “These authors showed that a recombinant N-terminal fragment of CRT (39-272) is a potent inducer of activation and maturation of B cells and macrophages and can trigger Ig class switching in B cells without T cell help in vitro and in vivo72.”