Chemokines are small chemoattractant cytokines that control a wide variety of biological and pathological processes, ranging from immunosurveillance to inflammation, and from viral infection to cancer. Genetic and pharmacological studies have shown that chemokines are responsible for the excessive recruitment of leucocytes to inflammatory sites and damaged tissue. In the present paper, we discuss the rationale behind interfering with the chemokine system and introduce various points for therapeutic intervention using either protein-based or small-molecule inhibitors. Unlike other cytokines, chemokines signal via seven-transmembrane GPCRs (G-protein-coupled receptors), which are favoured targets by the pharmaceutical industry, and, as such, they are the first cytokines for which small-molecule-receptor antagonists have been developed. In addition to the high-affinity receptor interaction, chemokines have an in vivo requirement to bind to GAGs (glycosaminoglycans) in order to mediate directional cell migration. Prevention of the GAG interaction has been shown to be a viable therapeutic strategy. Targeting chemokine intracellular signalling pathways offers an alternative small-molecule approach. One of the key signalling targets downstream of a variety of chemokine receptors identified to date is PI3Kγ (phosphoinositide 3-kinase γ), a member of the class I PI3K family. Thus the chemokine system offers many potential entry points for innovative anti-inflammatory therapies for autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis and allergic contact dermatitis.
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April 2004
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Conference Article|
April 01 2004
Chemokine inhibition – why, when, where, which and how?
Z. Johnson;
Z. Johnson
Serono Pharmaceutical Research Institute, Serono International, 14 Chemin des Aulx, CH 1228 Geneva, Switzerland
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C.A. Power;
C.A. Power
Serono Pharmaceutical Research Institute, Serono International, 14 Chemin des Aulx, CH 1228 Geneva, Switzerland
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C. Weiss;
C. Weiss
Serono Pharmaceutical Research Institute, Serono International, 14 Chemin des Aulx, CH 1228 Geneva, Switzerland
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F. Rintelen;
F. Rintelen
Serono Pharmaceutical Research Institute, Serono International, 14 Chemin des Aulx, CH 1228 Geneva, Switzerland
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H. Ji;
H. Ji
Serono Pharmaceutical Research Institute, Serono International, 14 Chemin des Aulx, CH 1228 Geneva, Switzerland
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T. Ruckle;
T. Ruckle
Serono Pharmaceutical Research Institute, Serono International, 14 Chemin des Aulx, CH 1228 Geneva, Switzerland
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M. Camps;
M. Camps
Serono Pharmaceutical Research Institute, Serono International, 14 Chemin des Aulx, CH 1228 Geneva, Switzerland
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T.N.C. Wells;
T.N.C. Wells
Serono Pharmaceutical Research Institute, Serono International, 14 Chemin des Aulx, CH 1228 Geneva, Switzerland
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M.K. Schwarz;
M.K. Schwarz
Serono Pharmaceutical Research Institute, Serono International, 14 Chemin des Aulx, CH 1228 Geneva, Switzerland
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A.E.I. Proudfoot;
A.E.I. Proudfoot
Serono Pharmaceutical Research Institute, Serono International, 14 Chemin des Aulx, CH 1228 Geneva, Switzerland
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C. Rommel
C. Rommel
1
Serono Pharmaceutical Research Institute, Serono International, 14 Chemin des Aulx, CH 1228 Geneva, Switzerland
1To whom correspondence should be addressed (e-mail christian.rommel@serono.com).
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Publisher: Portland Press Ltd
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2004 Biochemical Society
2004
Biochem Soc Trans (2004) 32 (2): 366–377.
Citation
Z. Johnson, C.A. Power, C. Weiss, F. Rintelen, H. Ji, T. Ruckle, M. Camps, T.N.C. Wells, M.K. Schwarz, A.E.I. Proudfoot, C. Rommel; Chemokine inhibition – why, when, where, which and how?. Biochem Soc Trans 1 April 2004; 32 (2): 366–377. doi: https://doi.org/10.1042/bst0320366
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