Abstract
IL-1β is a pleotropic cytokine that may mediate increased procoagulant activity and permeability in endothelial tissue during inflammatory conditions. The procoagulant effects of IL-1β are mediated through induction of tissue factor (TF) but its alterations on vascular permeability are not well characterized. We found that IL-1β induced a rapid and dose-dependent increase in TF activity in human umbilical vein endothelial cells (ECs) under routine culture conditions. However, IL-1β caused a rapid and marked increase in permeability across confluent EC monolayers using a two-compartment in vitro model only in the presence of factor VIII-deficient plasma that was completely abrogated by neutralizing anti-TF antibody pre-treatment. In vitro permeability was associated with loss of EC surface expression of VE-cadherin and contraction of F-actin cytoskeletal elements that resulted in EC intercellular gap formation. These data demonstrate that IL-1β induces marked changes in permeability across activated endothelium via a TF dependent mechanism and suggest that modulation of TF activity may represent a strategy to treat various acute and chronic inflammatory conditions mediated by this cytokine.
Highlights
IL-1β is a pleotropic 17.5 kD cytokine, secreted primarily by monocytes and macrophages, that mediates the pathophysiology of various acute and chronic inflammatory conditions
tissue factor (TF) induction and permeability in endothelial cells by IL-1β in vitro TF induction in ECs was assessed under basal culture conditions using a single-stage coagulation assay after a 2hour exposure to various concentrations of IL-1β
There was little TF activity measured at concentrations of IL-1β below 100 pg/mL and no further increase in TF activity was observed above 1 ng/ml
Summary
IL-1β is a pleotropic 17.5 kD cytokine, secreted primarily by monocytes and macrophages, that mediates the pathophysiology of various acute and chronic inflammatory conditions. High levels of circulating IL-1 have been identified in experimental models of endotoxic shock and acute bacterial infection and increased gene expression of IL-1 has been identified in tissues at sites of experimentally induced inflammation [1,2]. High levels of circulating IL-1 have been identified in patients with acute bacterial infections and elevated levels of IL-1 have been detected in the diseased articular tissues of patients with chronic rheumatoid arthritis [3,4]. Increased vascular permeability most likely represents the initial event in pathological or reparative inflammation or angiogenesis by allowing efflux of plasma proteins into interstitium to serve as a provisional matrix for circulating inflammatory cells or activated endothelium [15]. In rodent or guinea pig models others have not demonstrated any independent effects of aerosolized or systemically administered IL-1 on pulmonary vascular permeability or injury [21,22]
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