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Examination of the function of RANTES, MIP-1α, and MIP-1β following interaction with heparin-like glycosaminoglycans

Lookup NU author(s): Professor Simi Ali, Dr Adrian Palmer, Sarah Fritchley, Professor John Kirby

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Abstract

Chemokines are a group of small proteins that have a variety of functions, including the activation and recruitment of immune cells during episodes of inflammation. In common with many cytokines, it has been observed that chemokines have the potential to bind heparin-like glycosaminoglycan molecules, which are normally expressed on proteoglycan components of the cell surface and extracellular matrix. The significance of this interaction for chemokine activity remains a subject of debate. In this study, Chinese hamster ovary cells were transfected separately with the human chemokine receptors CCR1 and CCR5, and these receptors were shown to induce an intracytoplasmic Ca2+ flux and cellular chemotaxis following stimulation with the natural CC chemokine ligands (MIP-1α, RANTES (regulated on activation normal T cell expressed), and MIP-1β). In further experiments, mutant CHO cells, with a defect in normal glycosaminoglycan (GAG) expression, were also transfected with, and shown to express similar levels of, CCR1 and CCR5. Although these receptors were functional, it was found that the mutant cells required exposure to higher concentrations of ligands than the wildtype cells in order to produce the same intracytoplasmic Ca2+ flux. Radioligand binding experiments demonstrated that specific chemokine receptors expressed by wild-type cells had a significantly greater affinity for MIP-1α than similar receptors expressed by GAG-deficient mutants. However, there was no significant difference between these cells in their affinity for RANTES or MIP-1β. In conclusion, it has been demonstrated clearly that GAG expression is not necessary for the biological activity of the chemokines MIP-1α, RANTES, or MIP-1β. However, the presence of cell surface GAGs does enhance the activity of low concentrations of these chemokines by a mechanism that appears to involve sequestration onto the cell surface.


Publication metadata

Author(s): Fritchley SJ; Kirby JA; Ali S; Palmer ACV; Banerjee B

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2000

Volume: 275

Issue: 16

Pages: 11721-11727

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology

URL: .http:dx.doi.org/10.1074/jbc.275.16.11721

DOI: 10.1074/jbc.275.16.11721

PubMed id: 10766793


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