- Poster presentation
- Open Access
High mobility group box 1: as a 'testament' mediator
Critical Care volume 9, Article number: P176 (2005)
In general, cells responded to stresses by the following hierarchy: (1) stored mediator release reaction phase (e.g. serotonin, histamine); (2) lipid mediator generation/release phase (e.g. PGs, LTs, endocannabinoids); (3) genomic reaction phase (e.g. self-defensive protein generation phase through NF-κB, AP-1 activation). As the last response, we propose (4) high mobility group box 1 (HMGB1) releases from necrotic cells.
In this study we present intracellular and intercellular dynamics of HMGB1, and their roles in the pathogenesis in inflammation and organ failures.
Methods and results
We developed a specific and sensitive HMGB1 assay by the ELISA method as presented elsewhere in this congress (Yakabe K, et al., P177). Using this assay method, we evaluated serum HMGB1 levels in patients with various diseases. As a whole, the HMGB1 concentrations were elevated in various diseases that were correlated to the severity of organic cellular damages. These include infections, trauma, surgical operations, malignancies, and so on. The marked increase of HMGB1 (>10 ng/ml) was suggestive of presence of severe organ damages. However, the increased level of HMGB1 was not always sustained at higher levels and resultant lethality – because in some cases we observed that the elevated levels of HMGB1 rapidly decreased to subnormal or normal ranges with resulting recovery of the illness. This result suggested the presence of degrading or clearance mechanism of the protein. Thus, we examined the fate of the increased level of HMGB1 in the circulation.
At present, we have identified at least three pathways to decrease as well as produce the clearance of the circulatory HMGB1. The first is the degradation of HMGB1 by plasmin. We found that plasmin efficiently degraded HMGB1. The second way is the endothelial-dependent HMGB1 degradation by protein 'X'. HMGB1 binds to endothelium and be degraded by 'X'. The third way is the binding of HMGB1 by specific binding sites on diverse cells. These may include RAGE and proteoglycans. By these three routes, HMGB1 may be efficiently sequestered from the circulation and localized and enriched to the damaged tissue. The HMGB1 in situ acted as a stem cell inducer resulting in repair of damaged tissue/organ.
HMGB1 is released from most necrotic cells and behaves as a 'testament' mediator because this protein may be released in necrotic tissues including infection, injury and so on. The localized HMGB1 may act as an immune adjuvant and stem cell chemoatractant as recently described, and may play an important role for self-defense and repair of damaged tissue. However, if the HMGB1 released in cellular necrotic lesions entered into the circulation, this may diffuse the inflammation, and result in 'metastasis' of inflammation and organ failures. Therefore, HMGB1 should be enriched in injury sites, inhibiting its diffusion. We propose that this HMGB1 sequestering system is composed of plasmin, syndecan and endothelium. When this HMGB1-sequestering system is impaired, HMGB1 will enter into the circulation and act as a mediator of organ failure.