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The pan‐chemokine inhibitor NR58‐3.14.3 abolishes tumour necrosis factor‐α accumulation and leucocyte recruitment induced by lipopolysaccharide in vivo
Author(s) -
Reckless Jill,
Tatalick Lauren M.,
Grainger David J.
Publication year - 2001
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1046/j.1365-2567.2001.01228.x
Subject(s) - chemokine , in vivo , lipopolysaccharide , immunology , monocyte , macrophage inflammatory protein , tumor necrosis factor alpha , biology , chemotaxis , inflammation , receptor , biochemistry , microbiology and biotechnology
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 n m ), macrophage inflammatory protein‐1α (MIP‐1α) (5 n m ), regulated on activation, normal T‐cell expressed and presumably secreted (RANTES) (20 n m ), stromal cell‐derived factor‐1α (SDF‐1α) (25 n m ) and interleukin‐8 (IL‐8) (30 n m ), but did not affect migration induced by N ‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP) or complement C5a (> 100 µ m ). 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.