The effects of inflammatory cytokines on lymphatic endothelial barrier function

Abstract

Proper lymphatic function is necessary for the transport of fluids, macromolecules, antigens and immune cells out of the interstitium. The lymphatic endothelium plays important roles in the modulation of lymphatic contractile activity and lymph transport, but it's role as a barrier between the lymph and interstitial compartments is less well understood. Alterations in lymphatic function have long been associated with edema and inflammation although the integrity of the lymphatic endothelial barrier during inflammation is not well-defined. In this paper we evaluated the integrity of the lymphatic barrier in response to inflammatory stimuli commonly associated with increased blood endothelial permeability. We utilized in vitro assays of lymphatic endothelial cell (LEC) monolayer barrier function after treatment with different inflammatory cytokines and signaling molecules including TNF-α, IL-6, IL-1β, IFN-γ and LPS. Moderate increases in an index of monolayer barrier dysfunction were noted with all treatments (20–60% increase) except IFN-γ which caused a greater than 2.5 fold increase. Cytokine-induced barrier dysfunction was blocked or reduced by the addition of LNAME, except for IL-1β and LPS treatments, suggesting a regulatory role for nitric oxide. The decreased LEC barrier was associated with modulation of both intercellular adhesion and intracellular cytoskeletal activation. Cytokine treatments reduced the expression of VE-cadherin and increased scavenging of β-catenin in the LECs and this was partially reversed by LNAME. Likewise the phosphorylation of myosin light chain 20 at the regulatory serine 19 site, which accompanied the elevated monolayer barrier dysfunction in response to cytokine treatment, was also blunted by LNAME application. This suggests that the lymphatic barrier is regulated during inflammation and that certain inflammatory signals may induce large increases in permeability.

Modeling the Time Course of the Tissue Responses to Intramuscular Long-acting Paliperidone Palmitate Nano-/Microcrystals and Polystyrene Microspheres in the Rat

“…efflux of leukocytes, macromolecules, and plasma filtrate; Cromer et al 2014;Alitalo and Carmeliet 2002). As is the case with blood vascular endothelial cells, it has been described that several of the inflammatory cytokines elevated in the current study (e.g., IL-1b, IL-6, and TNF-a) can increase lymphatic endothelial cell permeability in vitro (Cromer et al 2014).…”

DeepCAGE transcriptomics identify HOXD10 as a transcription factor regulating lymphatic endothelial responses to VEGF-C

“…High HOXD10 expression resulted in abnormal junctions and increased permeability, whereas HOXD10 depletion resulted in reduced permeability through LEC monolayers. Currently, the role of VEGFR-3 signaling in regulating LEC permeability in vitro is not entirely clear, with some reports showing a reduction in transendothelial electric resistance of LECs after stimulation with VEGF-C (Breslin et al, 2007;Tacconi et al, 2015), whereas others found no effect of VEGF-C156S on macromolecular permeability (Cromer et al, 2014). Therefore, it is possible that wild-type VEGF-C induces permeability by activating VEGFR-2, whereas specific VEGFR-3 activation by VEGF-C156S has no such effects.…”

High-Fat Diet in the Absence of Obesity Does Not Aggravate Surgically Induced Lymphoedema in Mice

“…Several studies reported that obesity and metabolic syndrome might impair lymphatic function via changing the levels of inflammatory stimuli that might alter endothelial barrier functions or diminish the contractility of lymphatic vessels [34]. For instance, Scallan and colleagues [35,36] reported that impaired nitric oxide signalling was responsible for lymphatic vascular disruption in type 2 diabetes and that the contractility of collecting lymphatic vessels was improved upon genetic deletion of basal nitric oxide synthase.…”