title: The pro-inflammatory cytokine TNF-α inhibits lymphatic pumping via activation of the NF-κB-iNOS signaling pathway.
abstract: Mesenteric lymphatic vessel pumping, important to propel lymph and immune cells from the intestinal interstitium to the mesenteric lymph nodes, is compromised during intestinal inflammation. The objective of this study was to test the hypothesis that the pro-inflammatory cytokine TNF-α, is a significant contributor to the inflammation-induced lymphatic contractile dysfunction, and to determine its mode of action.
  
  
  
  Contractile parameters were obtained from isolated rat mesenteric lymphatic vessels mounted on a pressure myograph after 24-hours incubation with or without TNF-α. Various inhibitors were administered, and quantitative real-time PCR, Western blotting, and immunofluorescence confocal imaging were applied to characterize the mechanisms involved in TNF-α actions.
  
  
  
  Vessel contraction frequency was significantly decreased after TNF-α treatment and could be restored by selective inhibition of NF-кB, iNOS, guanylate cyclase, and ATP-sensitive K+channels. We further demonstrated that NF-кB inhibition also suppressed the significant increase in iNOS mRNA observed in TNF-α-treated lymphatic vessels and that TNF-α treatment favored the nuclear translocation of the p65 NF-κB subunit.
  
  
  
  These findings suggest that TNF-α decreases mesenteric lymphatic contractility by activating the NF-κB-iNOS signaling pathway. This mechanism could contribute to the alteration of lymphatic pumping reported in intestinal inflammation.
authors.affiliation: Inflammation Research Network, Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Yingxuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Inflammation Research Network, Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Sonia
authors.initials: S
authors.lastname: Rehal
authors.affiliation: Inflammation Research Network, Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Roizes
authors.affiliation: Smooth Muscle Research Group, Department of Physiology & Pharmacology, Libin Cardiovascular Institute & Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Hai-Lei
authors.initials: HL
authors.lastname: Zhu
authors.affiliation: Smooth Muscle Research Group, Department of Physiology & Pharmacology, Libin Cardiovascular Institute & Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: William C
authors.initials: WC
authors.lastname: Cole
authors.affiliation: Inflammation Research Network, Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Pierre-Yves
authors.identifier: 0000-0002-6020-393X
authors.initials: PY
authors.lastname: von der Weid
mesh_terms: D000818:Animals; D007249:Inflammation / Q000378:metabolism; D042601:Lymphatic Vessels / Q000503:physiopathology*; D008643:Mesentery / Q000098:blood supply; D009119:Muscle Contraction / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat
keywords: cytokine; inflammation; lymphatic vessel contraction; nitric oxide synthase; nuclear factor-kappa B