Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Feb 7;18(2):342.
doi: 10.3390/ijms18020342.

Mechanisms of Regulation of the Chemokine-Receptor Network

Martin J Stone  1   2 , Jenni A Hayward  3   4 , Cheng Huang  5   6 , Zil E Huma  7   8 , Julie Sanchez  9   10
Affiliations
Review

Mechanisms of Regulation of the Chemokine-Receptor Network

Martin J Stone et al. Int J Mol Sci. .

Abstract

The interactions of chemokines with their G protein-coupled receptors promote the migration of leukocytes during normal immune function and as a key aspect of the inflammatory response to tissue injury or infection. This review summarizes the major cellular and biochemical mechanisms by which the interactions of chemokines with chemokine receptors are regulated, including: selective and competitive binding interactions; genetic polymorphisms; mRNA splice variation; variation of expression, degradation and localization; down-regulation by atypical (decoy) receptors; interactions with cell-surface glycosaminoglycans; post-translational modifications; oligomerization; alternative signaling responses; and binding to natural or pharmacological inhibitors.

Keywords: binding; chemokine; chemokine receptor; expression; glycosaminoglycan; inhibitor; oligomerization; post-translational modification; regulation; signaling.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic overview of regulation mechanisms of the chemokine-receptor network. Abbreviations: PTM: post-translational modification; RBC: red blood cell. Arrows in red, purple, green and orange indicate processes involving chemokines, chemokine receptors, viral chemokines and atypical receptors, respectively.
Figure 2
Figure 2
The human chemokine-receptor network. Human chemokines and receptors are listed with symbols indicating whether they are specified as agonists or antagonists (or not specified) in the IUPHAR database. Note that, although CXCL1 is listed as a CXCR1 agonist in IUPHAR, the database reference suggests that it is actually an antagonist [11].
Figure 3
Figure 3
Structural basis of chemokine-receptor recognition. (a) One monomer unit of the receptor CXCR4 (PDB code 4RWS [14]) with extracellular regions labeled; transmembrane helices are colored salmon (I), orange (II), yellow (III), green (IV), turquoise (V), violet (VI), and magenta (VII). (b) A typical chemokine monomeric unit (CCL2/MCP-1, PDB code 1DOK [18]) highlighting the critical regions for receptor recognition. (c) Structure of CXCR4 bound to vMIPII (PDB code 4RWS [14]) showing the chemokine in pink (N-terminal region in hot pink) and the receptor in gray, with residues proposed to be involved in transmembrane signaling [19] colored according to their putative roles: blue, chemokine engagement; green, signal initiation; yellow, signal propagation; red, microswitch residues; magenta, G protein coupling. In panels (a,c) residues 1-22 are not shown as they were not modeled in the crystal structure.
Figure 4
Figure 4
Examples of post-translationally modified amino acid residues found in chemokines and chemokine receptors.
Figure 5
Figure 5
Oligomeric structures of chemokines. (a,b) Dimer structures of (a) CXCL8/IL-8 and (b) CCL2/MCP-1, highlighting the distinct dimer interfaces for CXC and CC chemokines, respectively. (c) Tetramer structure of CCL2, highlighting: (left) the CXC-type dimer interfaces (cyan to gray and magenta to yellow protomers); (center) the CC-type dimer interfaces (cyan to magenta and yellow to gray protomers); and (right) the highly electropositive (dark blue) surface involved in GAG binding.
Figure 6
Figure 6
Schematic representation of biased agonism. The red chemokine (left) selectively activates pathway 1, whereas the blue chemokine (right) selectively activates pathway 2.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Moser B., Wolf M., Walz A., Loetscher P. Chemokines: Multiple levels of leukocyte migration control. Trends Immunol. 2004;25:75–84. doi: 10.1016/j.it.2003.12.005. - DOI - PubMed
    1. Baggiolini M. Chemokines in pathology and medicine. J. Intern. Med. 2001;250:91–104. doi: 10.1046/j.1365-2796.2001.00867.x. - DOI - PubMed
    1. Gerard C., Rollins B.J. Chemokines and disease. Nat. Immunol. 2001;2:108–115. doi: 10.1038/84209. - DOI - PubMed
    1. Dimberg A. Chemokines in angiogenesis. Curr. Top. Microbiol. Immunol. 2010;341:59–80. - PubMed
    1. Speyer C.L., Ward P.A. Role of endothelial chemokines and their receptors during inflammation. J. Invest. Surg. 2011;24:18–27. doi: 10.3109/08941939.2010.521232. - DOI - PubMed

MeSH terms

LinkOut - more resources