Stimulation of alpha7 nicotinic acetylcholine receptor by nicotine attenuates inflammatory response in macrophages and improves survival in experimental model of sepsis through heme oxygenase-1 induction.

Abstract

Activation of nicotinic acetylcholine receptor alpha7 subunit (α7nAChR) by nicotine leads to the improved survival rate in experimental model of sepsis. Previously, we demonstrated that heme oxygenase (HO)-1 inducers or carbon monoxide significantly increased survival of lipopolysaccharide (LPS)-induced and cecal ligation and puncture-induced septic mice by reduction of high mobility group box 1 release, a late mediator of sepsis. However, that activation of α7nAChR by nicotine provides anti-inflammatory action through HO-1 upregulation has not been elucidated. Here we show that HO-1-inducible effect by nicotine was mediated through sequential event-Ca(2+) influx, classical protein kinase C activation, and reactive oxygen species production-which activates phosphoinositol-3-kinase/Akt/Nrf-2 pathway. In addition, HO-1 is required for nicotine-mediated suppression of tumor necrosis factor-α, inducible nitric oxide synthase, and high mobility group box 1 expression induced by LPS in macrophages, as evidenced by the fact that nicotine failed to inhibit production of these mediators when HO-1 was suppressed. Importantly, nicotine-induced survival rate was reduced by inhibition of HO-1 in LPS- and cecal ligation and puncture-treated septic mice. Collectively, these data suggest that activation of α7nAChR by nicotine is critical in the regulation of anti-inflammatory process, which could be mediated through HO-1 expression. Thus, we conclude that activation of α7nAChR by nicotine provides anti-inflammatory action through HO-1 upregulation.

• Authors: Konstantin Tsoyi, Hwa Jin Jang, Jong Woo Kim, Hong Kyung Chang, Young Soo Lee, Hyun-Ock Pae, Hye Jung Kim, Han Geuk Seo, Jae Heun Lee, Hun-Taeg Chung, Ki Churl Chang
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 14 Issue 11 Pg. 2057-70 (Jun 2011) ISSN: 1557-7716 [Electronic] United States
• PMID: 21083424 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Chrna7 protein, human
• Chrna7 protein, mouse
• HMGB1 Protein
• Lipopolysaccharides
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Nicotinic Agonists
• Reactive Oxygen Species
• Receptors, Nicotinic
• Tumor Necrosis Factor-alpha
• alpha7 Nicotinic Acetylcholine Receptor
• Nicotine
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• Heme Oxygenase-1
• NADPH Oxidases
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Protein Kinase C

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Calcium Signaling (drug effects)
• Cell Line
• Endotoxemia (genetics, metabolism)
• Gene Expression Regulation (drug effects)
• HMGB1 Protein (metabolism)
• Heme Oxygenase-1 (antagonists & inhibitors, genetics, metabolism)
• Humans
• Inflammation (chemically induced, prevention & control)
• Kaplan-Meier Estimate
• Lipopolysaccharides (toxicity)
• Macrophages (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• NADPH Oxidases (metabolism)
• NF-E2-Related Factor 2 (metabolism)
• Nicotine (pharmacology)
• Nicotinic Agonists (pharmacology)
• Nitric Oxide Synthase Type II (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Kinase C (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Reactive Oxygen Species (metabolism)
• Receptors, Nicotinic (metabolism)
• Sepsis (genetics, metabolism)
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (metabolism)
• alpha7 Nicotinic Acetylcholine Receptor