The CXC chemokines growth-regulated oncogene (GRO) α, GROβ, GROγ, neutrophil-activating peptide-2, and epithelial cell-derived neutrophil- activating peptide-78 are potent agonists for the type B, but not the type A, human interleukin-8 receptor

Sunil K Ahuja, Philip M. Murphy

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Abstract

Interleukin-8 (IL-8), growth-related oncogene (GRO) α, GROβ, GROγ, neutrophil-activating peptide-2 (NAP-2), epithelial cell-derived neutrophil activating peptide-78 (ENA-78), and granulocyte chemoattractant protein-2 are potent neutrophil chemoattractants 40-90% identical in amino acid sequence that comprise a subgroup of human CXC chemokines defined by the conserved sequence motif glutamic acid-leucine-arginine (ELR). Two human chemotactic receptor subtypes for IL-8, named IL-8 receptors (IL8R) A and B, have been cloned. They are 78% identical in amino acid sequence, coexpressed in neutrophils, and distinguished by their different selectivities for GROa and NAP-2. Their selectivity for other ELR+ CXC chemokines has not been previously reported. By measuring calcium flux in human embryonic kidney 293 cells transfected with plasmids encoding IL8RA or IL8RB, we have now defined receptor selectivity for GROβ, GROγ, and ENA-78. The rank order of agonist potency, based on inspection of the mean effective concentration values (EC50), for IL8RB was GROγ (1 nM) > IL-8 (4 nM) ~ GROα (5 nM) ~ GROβ (4 nM) ~ NAP-2 (7 nM) > ENA-78 (11 nM), and for IL8RA was IL-8 (4 nM) > > > ENA-78 (40 nM) ~ NAP-2 (45 nM) > GROα (63 nM)~GROγ (65 nM) >> GROβ. The maximal response of IL8RA to IL-8 was at least 2-fold greater than the other five chemokines. All six agonists for IL8RB competed for high affinity 125I-IL-8, -GROα, -NAP-2, and -ENA-78 binding sites at IL8RB. GROα, GROβ, GROγ, NAP-2, and ENA-78 competed weakly for the high affinity IL-8 binding site at IL8RA. Thus, IL8RA and IL8RB are both highly selective for IL-8 and have similar sequences but differ dramatically in their selectivity for all other ELR+ CXC chemokines tested. These findings have important implications for developing novel neutrophil-specific anti-inflammatory drugs directed against the CXC chemokine signaling system.

Original languageEnglish (US)
Pages (from-to)20545-20550
Number of pages6
JournalJournal of Biological Chemistry
Volume271
Issue number34
DOIs
StatePublished - Aug 23 1996

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Interleukin-8 Receptors
CXC Chemokines
Oncogenes
Neutrophils
Epithelial Cells
Interleukin-8
Growth
Chemotactic Factors
connective tissue-activating peptide
peptide 78
Interleukin-4
Amino Acid Sequence
Interleukin-8B Receptors
Binding Sites
Amino Acids
Conserved Sequence

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

@article{49dd2c4056f542419a1c4966e2dff174,
title = "The CXC chemokines growth-regulated oncogene (GRO) α, GROβ, GROγ, neutrophil-activating peptide-2, and epithelial cell-derived neutrophil- activating peptide-78 are potent agonists for the type B, but not the type A, human interleukin-8 receptor",
abstract = "Interleukin-8 (IL-8), growth-related oncogene (GRO) α, GROβ, GROγ, neutrophil-activating peptide-2 (NAP-2), epithelial cell-derived neutrophil activating peptide-78 (ENA-78), and granulocyte chemoattractant protein-2 are potent neutrophil chemoattractants 40-90{\%} identical in amino acid sequence that comprise a subgroup of human CXC chemokines defined by the conserved sequence motif glutamic acid-leucine-arginine (ELR). Two human chemotactic receptor subtypes for IL-8, named IL-8 receptors (IL8R) A and B, have been cloned. They are 78{\%} identical in amino acid sequence, coexpressed in neutrophils, and distinguished by their different selectivities for GROa and NAP-2. Their selectivity for other ELR+ CXC chemokines has not been previously reported. By measuring calcium flux in human embryonic kidney 293 cells transfected with plasmids encoding IL8RA or IL8RB, we have now defined receptor selectivity for GROβ, GROγ, and ENA-78. The rank order of agonist potency, based on inspection of the mean effective concentration values (EC50), for IL8RB was GROγ (1 nM) > IL-8 (4 nM) ~ GROα (5 nM) ~ GROβ (4 nM) ~ NAP-2 (7 nM) > ENA-78 (11 nM), and for IL8RA was IL-8 (4 nM) > > > ENA-78 (40 nM) ~ NAP-2 (45 nM) > GROα (63 nM)~GROγ (65 nM) >> GROβ. The maximal response of IL8RA to IL-8 was at least 2-fold greater than the other five chemokines. All six agonists for IL8RB competed for high affinity 125I-IL-8, -GROα, -NAP-2, and -ENA-78 binding sites at IL8RB. GROα, GROβ, GROγ, NAP-2, and ENA-78 competed weakly for the high affinity IL-8 binding site at IL8RA. Thus, IL8RA and IL8RB are both highly selective for IL-8 and have similar sequences but differ dramatically in their selectivity for all other ELR+ CXC chemokines tested. These findings have important implications for developing novel neutrophil-specific anti-inflammatory drugs directed against the CXC chemokine signaling system.",
author = "Ahuja, {Sunil K} and Murphy, {Philip M.}",
year = "1996",
month = "8",
day = "23",
doi = "10.1074/jbc.271.34.20545",
language = "English (US)",
volume = "271",
pages = "20545--20550",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
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TY - JOUR

T1 - The CXC chemokines growth-regulated oncogene (GRO) α, GROβ, GROγ, neutrophil-activating peptide-2, and epithelial cell-derived neutrophil- activating peptide-78 are potent agonists for the type B, but not the type A, human interleukin-8 receptor

AU - Ahuja, Sunil K

AU - Murphy, Philip M.

PY - 1996/8/23

Y1 - 1996/8/23

N2 - Interleukin-8 (IL-8), growth-related oncogene (GRO) α, GROβ, GROγ, neutrophil-activating peptide-2 (NAP-2), epithelial cell-derived neutrophil activating peptide-78 (ENA-78), and granulocyte chemoattractant protein-2 are potent neutrophil chemoattractants 40-90% identical in amino acid sequence that comprise a subgroup of human CXC chemokines defined by the conserved sequence motif glutamic acid-leucine-arginine (ELR). Two human chemotactic receptor subtypes for IL-8, named IL-8 receptors (IL8R) A and B, have been cloned. They are 78% identical in amino acid sequence, coexpressed in neutrophils, and distinguished by their different selectivities for GROa and NAP-2. Their selectivity for other ELR+ CXC chemokines has not been previously reported. By measuring calcium flux in human embryonic kidney 293 cells transfected with plasmids encoding IL8RA or IL8RB, we have now defined receptor selectivity for GROβ, GROγ, and ENA-78. The rank order of agonist potency, based on inspection of the mean effective concentration values (EC50), for IL8RB was GROγ (1 nM) > IL-8 (4 nM) ~ GROα (5 nM) ~ GROβ (4 nM) ~ NAP-2 (7 nM) > ENA-78 (11 nM), and for IL8RA was IL-8 (4 nM) > > > ENA-78 (40 nM) ~ NAP-2 (45 nM) > GROα (63 nM)~GROγ (65 nM) >> GROβ. The maximal response of IL8RA to IL-8 was at least 2-fold greater than the other five chemokines. All six agonists for IL8RB competed for high affinity 125I-IL-8, -GROα, -NAP-2, and -ENA-78 binding sites at IL8RB. GROα, GROβ, GROγ, NAP-2, and ENA-78 competed weakly for the high affinity IL-8 binding site at IL8RA. Thus, IL8RA and IL8RB are both highly selective for IL-8 and have similar sequences but differ dramatically in their selectivity for all other ELR+ CXC chemokines tested. These findings have important implications for developing novel neutrophil-specific anti-inflammatory drugs directed against the CXC chemokine signaling system.

AB - Interleukin-8 (IL-8), growth-related oncogene (GRO) α, GROβ, GROγ, neutrophil-activating peptide-2 (NAP-2), epithelial cell-derived neutrophil activating peptide-78 (ENA-78), and granulocyte chemoattractant protein-2 are potent neutrophil chemoattractants 40-90% identical in amino acid sequence that comprise a subgroup of human CXC chemokines defined by the conserved sequence motif glutamic acid-leucine-arginine (ELR). Two human chemotactic receptor subtypes for IL-8, named IL-8 receptors (IL8R) A and B, have been cloned. They are 78% identical in amino acid sequence, coexpressed in neutrophils, and distinguished by their different selectivities for GROa and NAP-2. Their selectivity for other ELR+ CXC chemokines has not been previously reported. By measuring calcium flux in human embryonic kidney 293 cells transfected with plasmids encoding IL8RA or IL8RB, we have now defined receptor selectivity for GROβ, GROγ, and ENA-78. The rank order of agonist potency, based on inspection of the mean effective concentration values (EC50), for IL8RB was GROγ (1 nM) > IL-8 (4 nM) ~ GROα (5 nM) ~ GROβ (4 nM) ~ NAP-2 (7 nM) > ENA-78 (11 nM), and for IL8RA was IL-8 (4 nM) > > > ENA-78 (40 nM) ~ NAP-2 (45 nM) > GROα (63 nM)~GROγ (65 nM) >> GROβ. The maximal response of IL8RA to IL-8 was at least 2-fold greater than the other five chemokines. All six agonists for IL8RB competed for high affinity 125I-IL-8, -GROα, -NAP-2, and -ENA-78 binding sites at IL8RB. GROα, GROβ, GROγ, NAP-2, and ENA-78 competed weakly for the high affinity IL-8 binding site at IL8RA. Thus, IL8RA and IL8RB are both highly selective for IL-8 and have similar sequences but differ dramatically in their selectivity for all other ELR+ CXC chemokines tested. These findings have important implications for developing novel neutrophil-specific anti-inflammatory drugs directed against the CXC chemokine signaling system.

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