Chemotaxins inhibit neutrophil adherence to and transmigration across cytokine‐activated endothelium: Correlation to the expression of L‐selectin

Abstract

Non-activated neutrophils strongly adhere to cytokine-activated human umbilical vein endothelial cells (HUVE). However, activation of neutrophils by different chemotactic mediators led to potent inhibition of this endothelial-dependent interaction. For different formylated peptides, concentrations leading to maximal adherence inhibition coincided with those known for inducing maximal chemotactic migration of neutrophils. In terms of maximal adherence inhibition, a rank list was found in the order of N-formyl-Met-Leu-Phe > C5adesArg > interleukin-8 > C5a > or = leukotriene B4, whereas platelet-activating factor, and lipopolysaccharide showed no inhibition. This rank order was congruent to that of down-regulation of neutrophil L-selectin detected by the monoclonal antibody Leu-8. Moreover, the dose-dependent increase of neutrophil adherence inhibition corresponded to the loss of L-selectin expression. Concentrations higher than that required for maximal inhibition led to a dose-dependent decrease of inhibition, which was accompanied by increasing expression of neutrophil CD11/CD18. In contrast to the capacity of non-activated neutrophils to migrate across interleukin-1-activated HUVE monolayers, transmigration was significantly impaired after chemotactic activation.

A peptide derived from neutrophil inhibitory factor (NIF) blocks neutrophil adherence to endothelial cells

“…The NIF peptides share no significant sequence identity with any known chemotactic factors. The ability of chemotactic agents to block neutrophil adherence has been described, but the mechanism of inhibition remains obscure [25][26][27]. The induction of shape change in neutrophils by such agents may be related 222 K. Madden et al…”

“…The morphology of neutrophils treated with fMLP or NIF224-252AA were indistinguishable (data not shown). It is interesting that fMLP and other potent chemotactic peptides such as IL-8 and C5a induce shape change and under certain conditions also inhibit neutrophil adherence [25][26][27]. The connection between induction of neutrophil shape change and anti-adherence activity was explored further for NIF224-252AA.…”

Control of Eosinophil Toxicity in the Lung

“…A further degree of selection is provided by the asthma-relevant cytokines IL-4 and IL-13. Stimulation of endothelial cells with either cytokine selectively upregulates VCAM-1 in the absence of expression of E-selectin or ICAM-1 and IL-4 also enhances eosinophil transmigration through endothelium in a VLA-4/VCAM-1-dependent manner [19,20]. Thus blocking the α4β1integrin/VCAM-1 pathway may provide a suitable target for preventing eosinophil accumulation in the lung.…”

The role of the epithelial cell in Escherichia coli induced neutrophil migration into the urinary tract

“…The mechanism behind the leucocyte adhesion inhibition (LAI) activity of IL-8 is unknown; however, its effects appear to be localized to the neutrophil and not the endothelial cell surface. IL-8 induced shedding of L-selectin has been proposed to play a role by preventing activated neutrophils from initiating the rolling event [77]. This is not likely to be the whole story, since IL-8 when delivered intravenously decreased the migratory capacity of rabbit neutrophils without inducing a significant loss of L-selectin [78].…”