Inhibitory Effects of TSG‐6 Link Module on Leukocyte–Endothelial Cell Interactions In Vitro and In Vivo

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Abstract
Objective: The authors investigated whether the anti‐inflammatory protein tumor necrosis factor (TNF)‐stimulated gene‐6 (TSG‐6) and its Link module (Link_TSG6) could affect the complex multistep process of leukocyte/endothelial cell (EC) interaction. Methods: Mouse mesenteries were inflamed with interleukin (IL)‐1β and the extent of leukocyte rolling, adhesion, and emigration was determined after 2 h. Link_TSG6 and a single‐point mutant (termed K13E) were given intraperitoneally together with the cytokine. Human neutrophil chemotaxis and transmigration were determined in vitro in response to IL‐8 and/or TNF‐α. TSG‐6, Link_TSG6, and K13E were added to the leukocytes or the EC monolayers. Results: Co‐injection of Link_TSG6 with IL‐1β selectively inhibited cell flux, adhesion, and emigration as analyzed in mesenteric postcapillary venules. The fewer cells that rolled in the animals treated with Link_TSG6 displayed a velocity similar to that measured in vehicle‐treated mice. In vitro, Link_TSG6 did not affect neutrophil chemotaxis or EC activation but did inhibit neutrophil transmigration across EC monolayers. The latter effect was shared by full‐length TSG‐6 and observed equally in response to IL‐8 or TNF‐α. Conclusions: These data restrict the site of action for at least some of the anti‐inflammatory effects ascribed to TSG‐6/Link_TSG6 to the microenvironment of the extravasating leukocyte.

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