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.

Ethyl Pyruvate Induces Heme Oxygenase-1 Through p38 Mitogen-Activated Protein Kinase Activation by Depletion of Glutathione in RAW 264.7 Cells and Improves Survival in Septic Animals

“…It has been already documented that the HO-1/CO system provides a therapeutic effect in many experimental pathological conditions (2,31). Recently, we and others demonstrated that HO-1/CO can improve survival and decrease the circulating HMGB1 level in septic animals, which further supports beneficial effects of HO-1 in inflammatory disorders (37,38,40).…”

“…Under the Nrf2 activation, it dissociates from Kelch-like ECHassociated protein 1 (Keap1) and translocates into the nucleus, where it binds ARE (18). Different pathways may activate Nrf2, including PI3K/Akt and MAPKs (6,13,38). We found that EP can activate Nrf2 by enhancing Nrf2 nuclear accumulation and the ARE-luciferase activity.…”

“…NO was measured as its stable oxidative metabolite, nitrite (NOx) as described previously (38). At the end of incubation, 100 ll of the culture medium was mixed with the same volume of Griess solution (0.1% naphthylethylenediamine and 1% sulfanilamide in 5% phosphoric acid).…”

Identification and Characterization of Poly(I:C)-induced Molecular Responses Attenuated by Nicotine in Mouse Macrophages

“…Moreover, the ELISA results complemented the RT-PCR array findings and vice versa. These results also indicate that transcriptional activation or repression of IL-6 and TNF-a (among others) following poly(I:C) stimulation or poly(I:C) 1 nicotine treatment accompanied an increase or decrease, respectively, in proinflammatory cytokines: an indication that gene activation or repression is involved in their actions, although other mechanisms (Tsoyi et al, 2011) could also be active. Similarly, antibody array results complement Western blotting findings and vice versa: CamKIIa phosphorylation was reduced in nicotine 1 poly(I:C)-treated cells in both assays.…”

The Microglial α7-Acetylcholine Nicotinic Receptor Is a Key Element in Promoting Neuroprotection by Inducing Heme Oxygenase-1 via Nuclear Factor Erythroid-2-Related Factor 2

“…Moreover, CO regulates monocyte/ macrophage activation (42), an effect associated with protection against different experimental models of disease (43,51). Induction of HO-1 expression by different nicotinic receptor agonists and its importance in the maintenance of antiinflammatory effects have been recently reported (57). On the other hand, induction of GCL-c, the rate-limiting enzyme of the novo synthesis of glutathione (GSH), by melatonin increases the levels of GSH and protects against oxidative stress (58).…”