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. 2008 May 20:5:6.
doi: 10.1186/1476-9255-5-6.

The tripeptide feG inhibits leukocyte adhesion

Ronald D Mathison  1 , Emily Christie, Joseph S Davison
Affiliations

The tripeptide feG inhibits leukocyte adhesion

Ronald D Mathison et al. J Inflamm (Lond). .

Abstract

Background: The tripeptide feG (D-Phe-D-Glu-Gly) is a potent anti-inflammatory peptide that reduces the severity of type I immediate hypersensitivity reactions, and inhibits neutrophil chemotaxis and adhesion to tissues. feG also reduces the expression of beta1-integrin on circulating neutrophils, but the counter ligands involved in the anti-adhesive actions of the peptide are not known. In this study the effects of feG on the adhesion of rat peritoneal leukocytes and extravasated neutrophils to several different integrin selective substrates were evaluated.

Results: The adhesion of peritoneal leukocytes and extravasated neutrophils from rats to adhesive proteins coated to 96-well plates was dependent upon magnesium (Mg2+) ion, suggestive of integrin-mediated adhesion. feG inhibited leukocyte adhesion, but only if the cells were stimulated with PAF (10-9M), indicating that feG's actions in vitro require cell activation. In the dose range of 10-10M to 10-12M feG inhibited the adhesion of peritoneal leukocytes to fibrinogen and fibronectin, but not IgG, vitronectin or ICAM-1. feG inhibited the binding of extravasated neutrophils to heparin, IgG, fibronectin and CD16 antibody. Antigen-challenge of sensitized rats reduced the adhesion of peritoneal leukocytes to most substrates and abolished the inhibitory effects of feG. However, pretreating the animals with intraperitoneal feG (100 mug/kg) 18 h before collecting the cells from the antigen-challenged animal restored the inhibition of adhesion by in vitro feG of peritoneal leukocytes and extravasated neutrophils to fibronectin.

Conclusion: The modulation of leukocyte adhesion by feG appears to involve actions on alphaMbeta2 integrin, with a possible interaction with the low affinity FcgammaRIII receptor (CD16). The modulation of cell adhesion by feG is dual in nature. When administered in vivo, feG prevents inflammation-induced reductions in cell adhesion, as well as restoring its inhibitory effect in vitro. The mechanism by which in vivo treatment with feG exerts these effects remains to be elucidated.

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Figures

Figure 1
Figure 1
PAF is required for inhibition of adhesion by feG. The inclusion of PAF (10-9M) was required to observe an inhibitory effect of feG (10-11M) on the adhesion of peritoneal leukocytes from unsensitized animals to fibrinogen and fibronectin. With extravasated neutrophils feG inhibition of adhesion only occurred in the presence of PAF for fibronectin. Control (black column), feG (open column; 10-11M), PAF (crossed column), and PAF + feG (lined column). Mean ± SEM; p < 0.05; * = less than corresponding controls; n ≥ 4 for each group of cells and substrate.
Figure 2
Figure 2
Effects of feG on the adhesion of peritoneal leukocytes to heparin, IgG, fibrinogen, fibronectin and vitronectin. Three different types of results are summarized: 1) the effects of antigen challenge (Ag); 2) the effects of in vivo treatment with feG (i.p. feG); and 3) the effects of ex vivo feG (open column). The adhesion, expressed as optical density (O.D.) for 1 million cells, is shown in the presence of PAF (10-9M) alone (black column), and in the presence of PAF and ex vivo feG (open column). The adhesion in the presence of ex vivo feG is the average adhesion for 10-10M to 10-12M feG added to the cells in the 96-well plate bars. Results are shown for four groups of animals: unsensitized (Unsens); unsensitized treated intraperitoneally with feG 18 h before harvesting the cells (Unsens + i.p. feG); antigen-challenged sensitized (Ag); and antigen-challenged sensitized treated intraperitoneally with feG 18 h before harvesting the cells (Ag + i.p. feG). Mean ± SEM; p < 0.05. # less than corresponding unsensitized group; χ greater than unsensitized group; * less than corresponding control (PAF alone); δ greater than no i.p. feG; X greater than corresponding unsensitized group. n ≥ 4 for each group of cells.
Figure 3
Figure 3
Effects of feG on the adhesion of carrageenan neutrophils to heparin, IgG, fibrinogen, fibronectin and vitronectin. Three different types of results are summarized: 1) the effects of antigen challenge (Ag); 2) the effects of in vivo treatment with feG (i.p. feG); and 3) the effects of ex vivo feG (open column). The adhesion, expressed as optical density (O.D.) for 1 million cells, is shown in the presence of PAF (10-9M) alone (black column), and in the presence of PAF and ex vivo feG (open column). The adhesion in the presence of ex vivo feG is the average adhesion for 10-10M to 10-12M feG added to the cells in the 96-well plate bars. Results are shown for four groups of animals: unsensitized (Unsens); unsensitized treated intraperitoneally with feG 18 h before harvesting the cells (Unsens + i.p. feG); antigen-challenged sensitized (Ag); and antigen-challenged sensitized treated intraperitoneally with feG 18 h before harvesting the cells (Ag + i.p. feG). Mean ± SEM; p < 0.05. # less than corresponding unsensitized group; χ greater than unsensitized group; * less than corresponding control (PAF alone); δ greater than no i.p. feG; X greater than corresponding unsensitized group. n ≥ 4 for each group of cells.
Figure 4
Figure 4
Dose-dependent inhibition of peritoneal leukocyte adhesion to fibrinogen and fibronectin. The inhibition of peritoneal leukocyte adhesion (OD/106 cells) to fibrinogen (black circles) and fibronectin (open circles) by 10-10M, 10-11M and 10-12M feG is shown for cells obtained from unsensitized rats that were either untreated (A) or pretreated with 100 μg/kg feG intraperitoneally 18 h before collecting the cells (B). Mean ± SEM; p < 0.05. * less than no feG in vitro (0). N ≥ 4.
Figure 5
Figure 5
Dose-dependent inhibition of neutrophil adhesion to antibodies. Inhibition by feG of the adhesion of extravasated neutrophils to CD11b (black circle) and CD16b (black square). Mean ± SEM; p < 0.05; * = significant inhibition. n ≥ 7 for each antibody and the different doses of feG.
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