Modulation of neutrophil function by the tripeptide feG

Ronald D Mathison,Joseph S Davison,A Befus,Richard C Woodman

doi:10.1186/1471-2172-4-3

Abstract

BackgroundNeutrophils are critical in the defense against potentially harmful microorganisms, but their excessive and inappropriate activation can contribute significantly to tissue damage and a worsening pathology. Through the release of endocrine factors submandibular glands contribute to achieving a balance in neutrophil function by modulating the state of activation and migratory potential of circulating neutrophils. A putative hormonal candidate for these effects on neutrophils was identified as a heptapeptide named submandibular gland peptide T (SGP-T; sequence = TDIFEGG). Since the tripeptide FEG, derived from SGP-T, and its D-amino acid analogue feG had similar inhibitory effects on inflammatory reactions, we investigated the effects of feG on human and rat neutrophil function.ResultsWith human neutrophils feG had no discernible effect on oxidative burst or phagocytosis, but in picomolar amounts it reduced PAF-induced neutrophil movement and adhesion, and the binding of CD11b by 34% and that of CD16b close to control values. In the rat feG (10-11M) reduced the binding of CD11b and CD16 antibodies to PAF-stimulated circulating neutrophils by 35% and 43%, respectively, and at 100 micrograms/kilograms intraperitoneally feG reduced neutrophil in vivo migration by 40%. With ovalbumin-sensitized rats that were challenged with antigen, feG inhibited binding of antibodies against CD16b but not CD11b, on peritoneal leukocytes.ConclusionsThe inhibitory effect of feG on neutrophil movement may be mediated by alterations in the co-stimulatory molecules CD11b and CD16.

Highlights

Neutrophils are critical in the defense against potentially harmful microorganisms, but their excessive and inappropriate activation can contribute significantly to tissue damage and a worsening pathology
The effects of different doses of feG on the migration of human neutrophils were examined over a 2 h period (Figure 1). feG, at doses ranging from 1011M to 10-9M, inhibited by 30 to 40% neutrophil migration elicited by platelet activating factor (PAF) (10-9M)
If the neutrophils were stimulated with 10-9M PAF, just prior to adding the neutrophils to the slides, adhesion increased by 64% from basal to 12.4 ± 1.4%, and feG at 10-11M and 10-10M inhibited neutrophil adhesion by 36% and 27%, respectively (Figure 2B)

Summary

Introduction

Neutrophils are critical in the defense against potentially harmful microorganisms, but their excessive and inappropriate activation can contribute significantly to tissue damage and a worsening pathology. From proximal N-terminal dibasic cleavage sites a pentapeptide, QHNPR, is generated that is involved in the modulation of mineral balance [2], whereas from the carboxyl-terminus a 7 amino acid peptide (TDIFEGG; SGP-T) is an inhibitor of endotoxic hypotension [3] and intestinal anaphylaxis [4]. This heptapeptide can be shortened to a biologically active pentapeptide (FEGGG) or tripeptide (FEG) [4]. The modulation of neutrophil activities constitutes an approach to regulate inflammatory responses, with the desired effect being a balance between the protective and tissue repair properties of neutrophils and their tissue destroying potential

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