HMGB1 is an early mediator of inflammation and may be negatively regulated by soluble receptor for advanced glycation end products in experimental endotoxinemia and in sepsis

Background

Cell membrane-bound receptor for advanced glycation end products (RAGE) is a major receptor for HMGB1. RAGE also circulates in soluble form – sRAGE, which binds circulating HMGB1 and inhibits its proinflammatory actions.

Materials

HMGB1, sRAGE, IL-6, IL-10 and TNFα levels were studied over 5 hours in 16 healthy volunteers exposed to endotoxin, and HMGB1 and sRAGE over 4 days in 45 patients with a diagnosis of severe sepsis or septic shock.

Methods

HMGB1 and sRAGE were measured using ELISA.

Results

Eleven out of 16 volunteers had measurable levels of HMGB1 at baseline, before endotoxin injection. Within 2 hours of endotoxin injection, parallel to the rise of IL-6, IL-10 and TNFα, HMGB1 increased more than fourfold in 12/16 volunteers (from baseline 0.52 (0 to 1.05) to 2.3 (1.63 to 4.42) (median, inter-quartile range)). In four volunteers, levels diminished after endotoxin was injected. sRAGE increased in all volunteers during the studied period. In 11 out of 16 volunteers, HMGB1 and sRAGE were released in patterns that seemed to be inversely related, suggesting mutual negative regulation. We went on to study release patterns of HMGB1 and sRAGE at days 0, 1 and 4 in patients with severe sepsis or septic shock. In 36/45 patients, the increase or decrease of HMGB1, between at least two time points, was opposite to the change in sRAGE levels, again suggesting mechanisms of negative regulation between the two.

Conclusion

(1) sRAGE and circulating HMGB1 have release patterns that suggest mutual negative regulation. Further studies are needed to evaluate sRAGE as a therapeutic means for reducing harmful HMGB1 levels in various inflammatory conditions. (2) HMGB1 is not only a late mediator of inflammation. It increased fourfold within 2 hours of endotoxin injection in healthy volunteers, parallel to the rise of IL-6, IL-10 and TNFα. (3) HMGB1 circulates at measurable levels in healthy individuals.