The pan‐chemokine inhibitor NR58‐3.14.3 abolishes tumour necrosis factor‐α accumulation and leucocyte recruitment induced by lipopolysaccharide in vivo

Summary Chemokines participate in the regulation of leucocyte recruitment in a wide variety of inflammatory processes, including host defence and diseases such as asthma, atherosclerosis and autoimmune disorders. We have previously described the properties of Peptide 3, the first broad‐specificity c...

Full description

Saved in:
Bibliographic Details
Published in:Immunology 2001-06, Vol.103 (2), p.244-254
Main Authors: Reckless, Jill, Tatalick, Lauren M., Grainger, David J.
Format: Article
Language:English
Subjects:
Animals
Chemokine CCL2 - antagonists & inhibitors
Chemokine CCL2 - immunology
Chemokines - antagonists & inhibitors
Dermatitis - immunology
Dermatitis - prevention & control
Drug Design
Female
Humans
Leukocytes - immunology
lipopolysaccharides
Lipopolysaccharides - antagonists & inhibitors
Lipopolysaccharides - immunology
Original
Peptides, Cyclic - chemistry
Peptides, Cyclic - pharmacology
Rats
Rats, Sprague-Dawley
Stereoisomerism
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha - immunology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Summary Chemokines participate in the regulation of leucocyte recruitment in a wide variety of inflammatory processes, including host defence and diseases such as asthma, atherosclerosis and autoimmune disorders. We have previously described the properties of Peptide 3, the first broad‐specificity chemokine inhibitor in vitro. Here, we report the properties of NR58‐3.14.3, a retroinverso analogue of Peptide 3. NR58‐3.14.3 inhibited leucocyte migration induced by a range of chemokines, including monocyte chemoattractant protein‐1 (MCP‐1) (2·5 nm), macrophage inflammatory protein‐1α (MIP‐1α) (5 nm), regulated on activation, normal T‐cell expressed and presumably secreted (RANTES) (20 nm), stromal cell‐derived factor‐1α (SDF‐1α) (25 nm) and interleukin‐8 (IL‐8) (30 nm), but did not affect migration induced by N‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP) or complement C5a (> 100 µm). NR58‐3.14.3 is therefore ≈ 1000‐fold more potent than Peptide 3 but retains the broad‐spectrum chemokine inhibitory activity of the parent peptide. In vivo, pretreatment with a systemic dose of 10 mg of NR58‐3.14.3, but not the inactive derivative NR58‐3.14.4, abolished leucocyte recruitment in response to intradermal injection of 500 ng of MCP‐1 into rat skin. This suggests that NR58‐3.14.3 is a functional chemokine inhibitor in vivo as well as in vitro. We utilized NR58‐3.14.3 as a tool to investigate the role of chemokine activity during leucocyte recruitment in response to lipopolysaccharide (LPS) in vivo. NR58‐3.14.3, but not NR58‐3.14.4, abolished leucocyte recruitment in response to intradermal injection of 50 ng of LPS into rat skin. Furthermore, NR58‐3.14.3 completely inhibited LPS‐induced accumulation of tumour necrosis factor‐α (TNF‐α). This data is consistent with a model in which multiple chemokines act in parallel upstream of TNF‐α. NR58‐3.14.3 is therefore a powerful anti‐inflammatory agent in vivo, suppressing proinflammatory cytokine production and leucocyte recruitment in response to endotoxin stimulus in rat skin.
ISSN:0019-2805
1365-2567
DOI:10.1046/j.1365-2567.2001.01228.x