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
. 2016 May 19:7:183.
doi: 10.3389/fimmu.2016.00183. eCollection 2016.

Modulation of Chemokine Responses: Synergy and Cooperativity

Amanda E I Proudfoot  1 , Mariagrazia Uguccioni  2
Affiliations
Review

Modulation of Chemokine Responses: Synergy and Cooperativity

Amanda E I Proudfoot et al. Front Immunol. .

Abstract

Chemokine biology is mediated by more complex interactions than simple monomolecular ligand-receptor interactions, as chemokines can form higher order quaternary structures, which can also be formed after binding to glycosaminoglycans (GAGs) on endothelial cells, and their receptors are found as dimers and/or oligomers at the cell surface. Due to the complexity of the chemokine binding and signaling system, several mechanisms have been proposed to provide an explanation for the synergy observed between chemokines in leukocyte migration. Pioneering studies on interactions between different chemokines have revealed that they can act as antagonists, or synergize with other chemokines. The synergism can occur at different levels, involving either two chemokine receptors triggered simultaneously or sequentially exposed to their agonists, or the activation of one type of chemokine receptor triggered by chemokine heterocomplexes. In addition to the several chemokines that, by forming a heterocomplex with chemokine receptor agonists, act as enhancers of molecules of the same family, we have recently identified HMGB1, an endogenous damage-associated molecular patterns (DAMPs) molecule, as an enhancer of the activity of CXCL12. It is now evident that synergism between chemokines is crucial at the very early stage of inflammation. In addition, the low-affinity interaction with GAGs has recently been shown to induce cooperativity allowing synergy or inhibition of activity by displacement of other ligands.

Keywords: cell migration; chemokines; glycosaminoglycan; oligomerization; synergy.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Synergism induced by the formation of heterocomplexes. (A) Heterocomplex formed between two chemokines renders the agonist more potent on the selective receptor. (B) HMGB1 forms a heterocomplex with CXCL12 enhancing CXCL12 potency on CXCR4.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med (2006) 354(6):610–21.10.1056/NEJMra052723 - DOI - PubMed
    1. Bachelerie F, Ben-Baruch A, Burkhardt AM, Combadiere C, Farber JM, Graham GJ, et al. International Union of Pharmacology. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharmacol Rev (2014) 66(1):1–79.10.1124/pr.113.007724 - DOI - PMC - PubMed
    1. Griffith JW, Sokol CL, Luster AD. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu Rev Immunol (2014) 32:659–702.10.1146/annurev-immunol-032713-120145 - DOI - PubMed
    1. Vacchini A, Locati M, Borroni EM. Overview and potential unifying themes of the atypical chemokine receptor family. J Leukoc Biol (2016).10.1189/jlb.2MR1015-477R - DOI - PubMed
    1. Zlotnik A. Chemokines and cancer. Int J Cancer (2006) 119(9):2026–9.10.1002/ijc.22024 - DOI - PubMed