title: Transforming growth factor-beta 1 inhibits the production of IL-8 and the transmigration of neutrophils through activated endothelium.
abstract: A central mechanism of inflammation is the activation of vascular endothelium by the inflammatory cytokines TNF-alpha and IL-1. These cytokines induce the expression of adhesion molecules, the elaboration of chemokines, and the transendothelial migration of white cells. TGF-beta 1 has anti-inflammatory properties, is expressed in the vessel wall, and has previously been shown to inhibit leukocyte adhesiveness to the endothelium at least in part by inhibiting the expression of E-selectin. We now show that TGF-beta 1 also inhibits the migration of neutrophils through endothelial monolayers activated by TNF-alpha. At a dose of 10 U/ml TNF-alpha, the transmigration of neutrophils was inhibited 42.7 +/- 7.9% (n = 8) by 0.2 ng/ml TGF-beta 1. Furthermore, TGF-beta 1 inhibited, in a time- and dose-dependent fashion, the elaboration of IL-8 by TNF-activated endothelial cells by between 33 and 78% (TNF doses from 100 down to 0.1 U/ml) and the elaboration of mRNA for IL-8 by 69%. TGF-beta 1 treatment did not significantly alter the TNF-induced IL-8 mRNA stability, suggesting that the mechanism of action of TGF-beta 1 is on gene transcription. Neutrophil transmigration through cytokine-activated endothelium involves both IL-8-dependent and IL-8-independent mechanisms. Using an anti-IL-8 Ab, we show that TGF-beta 1 inhibits only the IL-8-dependent pathway, but does not affect the IL-8-independent transendothelial migration mechanism. These and our previous results show that TGF-beta1, achieves its anti-inflammatory properties by inhibiting the expression of at least two genes, E-selectin and IL-8, which are essential in the inflammatory pathway.
authors.affiliation: Vascular Biology Unit, Hanson Centre for Cancer Research, Institute of Medical and Veterinary Science, Adelaide, Australia.
authors.forename: W B
authors.initials: WB
authors.lastname: Smith
authors.forename: L
authors.initials: L
authors.lastname: Noack
authors.forename: Y
authors.initials: Y
authors.lastname: Khew-Goodall
authors.forename: S
authors.initials: S
authors.lastname: Isenmann
authors.forename: M A
authors.initials: MA
authors.lastname: Vadas
authors.forename: J R
authors.initials: JR
authors.lastname: Gamble
mesh_terms: D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014471:Umbilical Veins
chemical_list: D016209:Interleukin-8; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha