ULLOA L, OCHANI M, WANG H, PAVLOV V, LIAO H, CZURA CJ, TRACEY KJ; Interscience Conference on Antimicrobial Agents and Chemotherapy (43rd: 2003: Chicago, Ill.).

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2003 Sep 14-17; 43: abstract no. B-1508.

North Shore-LIJ Research Institute, Manhasset, NY.

BACKGROUND: TNF is a validated therapeutic target for rheumatoid arthritis and Crohn's disease, and systemic inflammation. Efferent vagus nerve signals prevent systemic inflammatory responses by inhibiting TNF release (Nature 405:458-62, 2000). Acetylcholine, the primary neurotransmitter of the vagus nerve, modulates macrophages through the nicotinic acetylcholine receptor alpha-7 subunit (nAChR) (Nature 421:384-388, 2003). The physiology and organ-specific nature of this mechanism is unknown. METHODS: Endotoxemic BALB/c mice or alpha-7 nAChR-deficient mice were subjected to vagus nerve stimulation (VNS) and/or splenectomy. TNF protein and transcription were measured by ELISA, RNA protection assay and RT-PCR in different organs. RESULTS: The highest organ TNF concentrations were found in the spleen (21.3 + 4.3 ng TNF/ g protein). Splenectomy prevented the clinical signs of endotoxemia including diarrhea, piloerection and death (Survival: Sham+LPS=28.6% vs. Splenectomy +LPS =95.2%; n=10; P <0.05). Prevention of endotoxin lethality in splenectomized mice was correlated with attenuation of systemic TNF ([TNF]/ml serum: Sham+LPS=157 + 35 pg/ml vs. Splenectomy +LPS = 47 + 11 pg/ml; n=7; P <0.05). Electrical stimulation of vagus nerve attenuates TNF production in the spleen ([TNF]/g spleenic protein: Sham+LPS=17 + 2.5 ng/g vs. VNS+LPS = 2.7 + 2 ng/g n=7; P <0.05). VNS fails to suppress splenic and therefore systemic TNF production in alpha-7 nAChR deficient mice ([TNF]/g splenic protein: sham+LPS=20 + 5.3 ng/ g vs. VNS+LPS = 29 + 6.4 ng/ g; P<0.05). CONCLUSIONS: Spleen is the major source of systemic TNF during endotoxemia and plays a critical physiological role in the regulation of systemic inflammation by the vagus nerve. Vagus nerve regulates systemic inflammation by regulating TNF transcription in the spleen through alpha-7 nAChR subunits.

Publication Types:

• Meeting Abstracts

Keywords:

• Acetylcholine
• Animals
• Electric Stimulation
• Endotoxemia
• Endotoxins
• Humans
• Inflammation
• Lipopolysaccharides
• Macrophages
• Mice
• Receptors, Nicotinic
• Spleen
• Splenectomy
• Vagus Nerve
• immunology
• surgery

Other ID:

• GWAIDS0025675

UI: 102265299

From Meeting Abstracts