Inhibitory effects of TSG-6 Link module on leukocyte-endothelial cell interactions in vitro and in vivo.
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)-1beta 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-alpha. TSG-6, Link_TSG6, and K13E were added to the leukocytes or the EC monolayers.


RESULTS
Co-injection of Link_TSG6 with IL-1beta 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-alpha.


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.
Cao
Thong V
TV
The William Harvey Research Institute, Bart's and the London Queen Mary School of Medicine and Dentistry, London, UK.
La
Mylinh
M
Getting
Stephen J
SJ
Day
Anthony J
AJ
Perretti
Mauro
M
D000818:Animals; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control; D007375:Interleukin-1 / Q000008:administration & dosage; D007962:Leukocytes / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D010538:Peritonitis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology
D015815:Cell Adhesion Molecules; D007375:Interleukin-1; D010446:Peptide Fragments; D011994:Recombinant Proteins; C072273:TNFAIP6 protein, human; C513057:Tnfaip6 protein, mouse