Korean J Anat.  2008 Mar;41(1):89-96.

Extracellular HMGB1 Released after Zinc-treatment Induces Neuronal Death in Primary Cortical Cultures

Affiliations
  • 1Department of Anatomy and Center for Advanced Medical Education (BK21 project), Inha University School of Medicine, Inchon, Korea. jklee@inha.ac.kr

Abstract

As a nonhistone DNA-binding protein, high mobility group box 1 (HMGB1) is released in large amounts into the extracellular space immediately after ischemic insult and plays a role in the release of proinflammatory cytokines. Here, we the examined cytokine-like or signaling molecule-like function of extracellular HMGB1 in primary cortical cultures. We found that a large amount of HMGB1 was released following zinc-induced neuronal cell death in primary cortical cultures and that this extracellular HMGB1 might aggravate neuronal damage. The conditioned media collected from zinc-treated primary cortical cultures decreased neuronal cell survival to 69.6+/-1.4% of control values when added to fresh primary cortical cultures. In contrast, treatment with HMGB1-depleted conditioned media produced by cultures treated with an HMGB1 siRNA-expression vector suppressed the induction of neuronal death. A mutant HMGB1 siRNA-expression vector did not suppress the induction of neuronal death, demonstrating a role of HMGB1 in neuronal death. Moreover, HMGB1-depletion in media conditioned by cotreatment with anti-HMGB1 antibody or with anti-RAGE antibody, a potential receptor for HMGB1, recovered neuronal cell survival to 81.0+/-4.0% and 79.0+/-4.0%, respectively, when added to fresh primary cortical cultures. These results indicate that extracellular HMGB1 released after zinc treatment induces neuronal death, which might aggravate zinc toxicity.

Keyword

Zinc; HMGB1; Primary cortical culture; Neuronal cell death

MeSH Terms

Cell Death
Cell Survival
Culture Media, Conditioned
Cytokines
Extracellular Space
HMGB1 Protein
Neurons
Zinc
Culture Media, Conditioned
Cytokines
HMGB1 Protein
Zinc
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