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N‐ and C‐terminal peptides of hIL‐8/CXCL8 are ligands for hCXCR1 and hCXCR2
Author(s) -
Li QiJing,
Yao Min,
Wong William,
Parpura Vladimir,
MartinsGreen Manuela
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-1175fje
Subject(s) - chemokine , chemotaxis , microbiology and biotechnology , chemokine receptor , receptor , cxc chemokine receptors , g protein coupled receptor , chemistry , biology , signal transduction , biochemistry
Chemokines are small cytokines that function in immune responses, wound healing, and pathological conditions such as chronic inflammation and tumorigenesis. This multifunctionality has been attributed primarily to ligand interaction with multiple or dimerized receptors. However, multifunctionality could also result from interactions of the receptors with small peptides produced by processing of the chemokines. Chemokine peptides are functional in vivo, but it is not yet known whether they can interact with and activate their receptors. The work presented here examines the interactions between the two forms of human interleukin 8 (hIL‐8), and its N‐ and C‐peptides, with the chemokine receptors hCXCR1 and hCXCR2. We used a Tet‐ on retroviral system to introduce CXCR1 into mouse NIH 3T3 cells (that lack endogenous CXCR1) and monitored activation of this receptor by the ligands by using quantitative Ca 2+ imaging and mitogen‐activated protein kinase (MAPK) activation. We found that the N and C termini of the chemokine can stimulate the respective CXCR1 to induce intracellular Ca 2+ release and MAPK activation independent of the other regions of the molecules. Furthermore, we showed that these peptides can also stimulate chemotaxis of several cell types, including primary human microvascular endothelial cells, and that this function is specific and mediated by hCXCR1 and/or hCXCR2. These findings advance understanding of the multifunctionality exhibited by chemokines, reveal a new mode of functional regulation, and may serve as the basis for therapeutic targeting.