Toru Kanke

Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats

The high mobility group box‐1 (HMGB1), originally identified as an architectural nuclear protein, exhibits an inflammatory cytokine‐like activity in the extracellular space. Here we show that treatment with neutralizing anti‐HMGB1 monoclonal antibody (mAb; 200 μg, twice) remarkably ameliorated brain infarction induced by 2‐h occlusion of the middle cerebral artery in rats, even when the mAb was administered after the start of reperfusion. Consistent with the 90% reduction in infarct size, the accompanying neurological deficits in locomotor function were significantly improved. Anti‐HMGB1 mAb inhibited the increased permeability of the blood‐brain barrier, the activation of microglia, the expression of TNF‐α and iNOS, and suppressed the activity of MMP‐9, whereas it had little effect on blood flow. Intracerebroventricular injection of HMGB1 increased the severity of infarction. Immunohistochemi‐cal studyrevealed that HMGB1 immunoreactivityin the cell nuclei decreased or disappeared in the affected areas, suggesting the release of HMGB1 into the extracellular space. These results indicate that HMGB1 plays a critical role in the development of brain infarction through the amplification of plural inflammatory responses in the ischemic region and could be an out‐standingly suitable target for the treatment. Intravenous injection of neutralizing anti‐HMGB1 mAb provides a novel therapeutic strategy for ischemic stroke.— Liu, K., Mori, S., Takahashi, H. K., Tomono, Y., Wake, H., Kanke, T., Sato, Y., Hiraga, N., Adachi, N., Yoshino, T., Nishibori, M. Anti‐high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats. FASEB J. 21, 3904–3916 (2007)

Effects of adenosine on adhesion molecule expression and cytokine production in human PBMC depend on the receptor subtype activated

Adenosine suppresses immune responses through adenosine2A (A2A) receptors, by raising intracellular cAMP. Interleukin (IL)‐18 up‐regulates the expression of intercellular adhesion molecule (ICAM)‐1 on monocytes, leading to production of pro‐inflammatory cytokines such as IL‐12, interferon (IFN)‐γ and tumor necrosis factor (TNF)‐α by human peripheral blood mononuclear cells (PBMC). We have previously demonstrated that elevation of cAMP inhibits this IL‐18‐induced expression of adhesion molecules. In the present study, we examined the effect of adenosine on the IL‐18‐induced up‐regulation of ICAM‐1 on human monocytes and production of IL‐12, IFN‐γ and TNF‐α by PBMC.

Stimulation of adenosine A2A receptor inhibits LPS-induced expression of intercellular adhesion molecule 1 and production of TNF-α in human peripheral blood mononuclear cells

LPS stimulates CD14/Toll-like receptor (TLR) 4, leading to induce TNF-&agr; production. Cell-to-cell interaction through the engagement between intercellular adhesion molecule (ICAM) 1 on monocytes and its ligand on T cells has been suggested to play a role in the TNF-&agr; production by LPS-treated human peripheral blood mononuclear cells (PBMCs). Adenosine is reported to inhibit LPS-induced TNF-&agr; production. However, little is known about the mechanism of the inhibitory effects induced by adenosine on the LPS-induced immune responses. We found that adenosine inhibited the expression of ICAM-1 and the production of TNF-&agr; by human PBMC via adenosine A2A receptor in the presence of LPS. However, the stimulation of A1R or A3R enhanced the actions of adenosine. Adenosine had no effect on the expression of CD14 and TLR-4, suggesting that the inhibitory effects of adenosine on the LPS actions might be independent of the expression of CD14 and TLR-4. Thus, adenosine differentially regulates the expression of ICAM-1 and the production of TNF-&agr; through plural subtypes of receptors.