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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
Article first published online: 21 DEC 2001
Volume 103, Issue 2, pages 244–254, June 2001
How to Cite
Reckless, J., Tatalick, L. M. and Grainger, D. J. (2001), The pan-chemokine inhibitor NR58-3.14.3 abolishes tumour necrosis factor-α accumulation and leucocyte recruitment induced by lipopolysaccharide in vivo. Immunology, 103: 244–254. doi: 10.1046/j.1365-2567.2001.01228.x
- Issue published online: 21 DEC 2001
- Article first published online: 21 DEC 2001
- Received 9 November 2000; revised 17 January 2001; accepted 2 February 2001.
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.