TNF‐α Inhibits Rat Mesenteric Lymphatic Pumping via Activation of the NF‐κB and Upregulation of iNOS

Abstract

Upregulated TNF‐α production and dysfunctional lymphatic pumping are observed in inflammatory bowel disease pathogenesis. It has been previously demonstrated that TNF‐α could decrease arterial contractility via activation of the inducible nitric oxide synthase (iNOS) and that iNOS is involved in impaired mesenteric lymphatic pumping in animal model of intestinal inflammation. We investigated the effects of TNF‐α on rat mesenteric lymphatic pumping and hypothesized that the cytokine may impair lymphatic contractile function during intestinal inflammation by upregulating the synthesis of iNOS and thus the production of nitric oxide.Using pressure myography, we examined the contractile function of isolated rat mesenteric lymphatic vessels following a 24‐hr treatment with TNF‐α. We observed that contraction frequency was significantly and concentration‐dependently decreased by TNF‐α, an effect restored following administration of inhibitors of NF‐κB (PDTC), iNOS (1400W), guanylate synthase (ODQ) and ATP‐sensitive K+ channels (glibenclamide), but not the cyclooxygenase inhibitor, indomethacin. The involvements of NF‐κB and iNOS were further confirmed by western blot analysis and quantitative real‐time PCR, which revealed upregulations of phospho‐IκB and iNOS mRNA in TNF‐α‐treated vessels that were minimized in the presence of PDTC.These findings suggest that TNF‐α decreases lymphatic contractility via activation of the NF‐κB‐iNOS pathway.