sincalide and Inflammatory-Bowel-Diseases

The recently proposed Inflammatory Reflex describes an interaction between the vagus nerve and peripheral macrophages, resulting in attenuation of proinflammatory cytokine release in response to systemic exposure to bacterial endotoxin. The purpose of this study was to determine whether a similar vagus/macrophage axis modulates the inflammatory responses in the colon in mice.. We assessed the Disease Activity Index (DAI), macroscopic and histologic damage, serum amyloid-P level, and myeloperoxidase activity in colitis induced by administration of dextran sodium sulfate (DSS) in healthy and vagotomized C57BL/6 and in mice deficient in macrophage-colony stimulating factor (M-CSF)-induced and in hapten-induced colitis. A pyloroplasty was performed in vagotomized mice.. DAI, macroscopic and histologic scores, myeloperoxidase activity, levels of serum amyloid-P, and colonic tissue levels of interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha were increased significantly in vagotomized mice 5 days post-DSS and 3 days after hapten-induced colitis compared with sham-operated mice that received DSS or the hapten. Pretreatment with nicotine significantly decreased each of these markers in vagotomized mice with DSS colitis, and all markers except DAI and IL-6 in sham-operated DSS-treated mice. Conversely, hexamethonium treatment significantly increased each of these markers in the sham-operated DSS-treated mice. Vagotomy had no effect on the colitis in M-CSF-deficient mice.. The vagus nerve plays a counterinflammatory role in acute colitis via a macrophage-dependent mechanism, involving hexamethonium-sensitive nicotinic receptors. The identification of a counterinflammatory neural pathway would open new therapeutic avenues for treating acute exacerbations of inflammatory bowel disease.

Topics: Animals; Anticoagulants; Appetite Depressants; Dextran Sulfate; Dinitrofluorobenzene; Disease Models, Animal; Eating; Ganglionic Blockers; Ganglionic Stimulants; Hexamethonium; Inflammatory Bowel Diseases; Macrophage Colony-Stimulating Factor; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Neural Inhibition; Nicotine; Pylorus; Sincalide; Vagotomy; Vagus Nerve

Plasma cholecystokinin increases with enteral feeding. Cholecystokinin increases intracellular calcium in lymphocytes/monocytes and is a lymphocyte co-mitogen. We hypothesize that decreased cholecystokinin production with "bowel rest" and parenteral nutrition may be beneficial in inflammatory bowel disease by down-regulating gut immune/inflammatory mechanisms. The majority of cells observed in mucosa of inflammatory bowel disease are monocytes and neutrophils. Cholecystokinin effect was therefore measured on monocyte production of proinflammatory mediators (tumor necrosis factor alpha, interleukin-1 beta, interleukin-6) and neutrophil chemotaxins/activators (interleukin-8, granulocyte-macrophage colony stimulating factor, and leukotriene B4).. Peripheral blood monocytes (0.5 x 10(6)) from healthy donors in 1 mL of RPMI 1640 plus 5% fetal calf serum were cultured for 24 h in 5% CO2 at 37 degrees C with 5 micrograms/mL endotoxin, 1 x 10(-7) M cholecystokinin, or no agonist. Supernatants were analyzed by ELISA for cytokines and leukotriene B4.. Endotoxin-stimulated monocytes produced 1130 pg/mL tumor necrosis factor versus 81 pg/mL for cholecystokinin, 612 pg/mL interleukin-1 versus 10 pg/mL, 694 pg/mL interleukin-6 versus 30 pg/mL, 4531 pg/mL of interleukin-8 versus 3848 pg/mL, 21 pg/mL granulocyte-macrophage colony stimulating factor versus 9 pg/mL, and 21 pg/mL leukotriene B4 versus 12 pg/mL. Controls produced no cytokines/eicosanoids (N = 8, p < 0.001).. Cholecystokinin increase with enteral feeding may up-regulate gut immune response. Cholecystokinin suppression with parenteral alimentation may decrease inflammatory mediator production.

Topics: Cells, Cultured; Cholecystokinin; Cytokines; Dose-Response Relationship, Drug; Eicosanoids; Enteral Nutrition; Enzyme-Linked Immunosorbent Assay; Humans; Inflammatory Bowel Diseases; Monocytes; Sincalide; Up-Regulation