The pro-inflammatory cytokine TNF-α inhibits lymphatic pumping via activation of the NF-κB-iNOS signaling pathway

ObjectiveMesenteric 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-, is a significant contributor to the inflammation-induced lymphatic contractile dysfunction, and to determine its mode of action. MethodsContractile parameters were obtained from isolated rat mesenteric lymphatic vessels mounted on a pressure myograph after 24-hours incubation with or without TNF-. Various inhibitors were administered, and quantitative real-time PCR, Western blotting, and immunofluorescence confocal imaging were applied to characterize the mechanisms involved in TNF- actions. ResultsVessel contraction frequency was significantly decreased after TNF- treatment and could be restored by selective inhibition of NF-kB, iNOS, guanylate cyclase, and ATP-sensitive K+ channels. We further demonstrated that NF-kB inhibition also suppressed the significant increase in iNOS mRNA observed in TNF--treated lymphatic vessels and that TNF- treatment favored the nuclear translocation of the p65 NF-B subunit. ConclusionsThese findings suggest that TNF- decreases mesenteric lymphatic contractility by activating the NF-B-iNOS signaling pathway. This mechanism could contribute to the alteration of lymphatic pumping reported in intestinal inflammation.