CHOLINE SUPPRESSES INFLAMMATORY RESPONSES

Parrish, W. R.*; Gallowitsch Puerta, M.*; Ochani, M.*; Ochani, K.*; Moskovic, D.*; Lin, X.*; Czura, C. J.; Miller, E. J.; Al-Abed, Y.*; Tracey, K. J.; Pavlov, V. A.

Abstracts

Laboratory of Biomedical Science, 1Department of Surgery, 2Laboratory of Medicinal Chemistry, The Feinstein Institute for Medical Research, Manhasset, NY 11030.

Systemic inflammation caused by excessive production of TNF and other pro-inflammatory cytokines is a hallmark of sepsis. Recent studies demonstrate that electrical stimulation of the efferent vagus nerve inhibits TNF production and attenuates systemic inflammation (Nature, 2000, 420:853; Nature, 2003, 421:384). The α7 nicotinic acetylcholine receptor (α7nAChR) expressed on macrophages plays a key role in mediating the vagal anti-inflammatory effect (Nature, 2003, 421:384). These findings suggest the therapeutic potential of specifically targeting the α7nAChR to activate endogenous immunoregulatory mechanisms to temper excessive inflammatory responses. Here we examined the ability of the endogenous and selective α7nAChR agonist choline to attenuate TNF production in vitro and in vivo. Choline (0.01 - 50 mM) dose-dependently inhibited TNF release from endotoxin-stimulated RAW 264.7 mouse macrophages and primary human macrophages, which express α7nAchR (Nat. Med., 2004, 10(11): 1216; Nature, 2003, 421:384). Inhibition of TNF production from RAW 264.7 macrophages correlated with attenuation of NF-κB activity, suggesting that NF-κB represents a downstream target of cholinergic anti-inflammatory signaling. Choline treatment (5 and 50 mg/kg, i.p.), 30 min prior to endotoxin administration (6 mg/kg, i.p.) in mice, dose-dependently reduced serum TNF levels. These data demonstrate the anti-inflammatory activity of choline, an endogenous α7nAChR agonist, and indicate its therapeutic potential in restraining excessive inflammation. This study was funded in part by a FIMR research award to VAP.

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