Abstract
Background: Venous thrombosis (VT) and the vein wall responses may be related to interleukin 6 (IL-6) signaling in humans and mice. Inflammatory and fibrotic effects of IL-6 largely signal through the trans pathway: IL-6/soluble IL-6Rα complex associates with ubiquitously expressed signal transducing protein gp130. We hypothesized that IL-6 signaling would differ depending upon thrombosis mechanism (complete v. partial stasis), and disruption of IL-6/IL-6Rα/gp130 axis would alter vein wall response to VT. Methods: Wild type C57BL/6 or IL-6-/- mice underwent induction of VT via inferior vena cava (IVC) stenosis (partial stasis) or ligation (complete stasis). Select WT mice received sgp130Fc chimera to inhibit trans pathway signaling. Vein wall, thrombus, and plasma were harvested at various time points and analyzed by PCR, western blot, ELISA or immunohistochemistry. Results: Compared to sham animals, those undergoing VT (complete or partial stasis) exhibited elevated vein wall IL-6 on post-VT day 4 (n=6-9, p<0.0001) but only complete stasis also had significantly elevated IL-6Rα (n=6-9, p<0.0001) and downstream intracellular signaling pathway molecule pSTAT3 (n=6-9, p=0.0002). Complete stasis VT in IL-6-/- mice was characterized by decreased circulating gp130 (n=4-6 p=0.0257), similar size thrombi to WT controls (0.020±0.005 v. 0.023±0.006, p=ns), and decreased CD68+ macrophage recruitment to the vein wall (n=3-5, p=0.0279). The IL-6-/- mice were protected from endothelial to mesenchymal-like transformation, as reflected by decreased FSP-1 (n=3-6, p<0.0001) and increased VE cadherin (n=3-6, p=0.0421) as compared with WT. Disruption of trans-signaling pathway via gp130Fc chimera resulted in less vein IL-6 (n=6-7, p=0.0027), TGF-β (n=6-7, p=0.0094), and decreased CD68 cell recruitment (n=3, p=0.0299). Conclusions: Experimental VT stimulates IL-6 and downstream signaling processes and is dependent on the mechanism of thrombosis. Genetic deletion of IL-6 and selective disruption of trans-signaling pathway by sgp130 decreases vein wall inflammation and influences vein wall remodeling. Targeting of IL-6 trans-signaling pathway may represent a therapeutic option to treat vein wall inflammation post thrombosis.
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