Endothelial activation in monosodium urate monohydrate crystal‐induced inflammation. In vitro and in vivo studies on the roles of tumor necrosis factor α and interleukin‐1

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Abstract
Objective. There is relatively little direct evidence for the roles of interleukin‐1 (IL‐1) and tumor necrosis factor α (TNFα) in activating endothelium in vivo. The aim of this study was to use in vitro and in vivo models to investigate the contribution of these cytokines to both E‐selectin expression and the recruitment of polymor‐phonuclear cells (PMN) in monosodium urate monohydrate (MSU) crystal‐induced inflammation.Methods. MSU crystals were incubated with freshly isolated mononuclear cells, after which the harvested supernatants were tested for their ability to induce E‐selectin expression during coculture with human umbilical vein endothelial cells. Subsequent experiments were performed with the addition of neutralizing anticytokine antibodies/antisera. The role of TNFα was then studied in an MSU crystal‐induced monarthritis model, in the presence or absence of anti‐TNFα (5 mg/kg intravenously). 99mtechnetium (99mTc)‐labeled PMN cells and 111indium (111In)‐labeled anti‐E‐selectin monoclonal antibody (MAb) 1.2B6 were intravenously administered 4 hours after intraarticular injection to quantify PMN recruitment and E‐selectin expression in inflamed joints.Results. MSU crystals were a potent stimulus for IL‐1 and TNFα production by monocytes in vitro, and these cytokines fully accounted for MSU crystalstimulated, monocyte‐mediated endothelial activation. In the MSU crystal‐induced monarthritis model, TNFα blockade was very effective in suppressing both E‐selectin expression and PMN emigration into the inflamed joints, as judged by gamma‐camera image analysis and postmortem tissue counting following the intravenous injection of 99mTc‐PMN and 111In‐anti‐E‐selectin MAb.Conclusion. IL‐1 and TNFα appear to be the only factors released by monocytes following incubation with MSU crystals, which induce E‐selectin expression in vitro. Anti‐TNFα is effective in suppressing endothelial activation and PMN recruitment in vivo E‐selectin imaging can be used to assess the endothelial response to therapy and may prove useful for clinical studies.