Gene copy number regulates the production of the human chemokine CCL3-L1

Townson, J. R., Barcellos, L. F. and Nibbs, R. J.B. (2002) Gene copy number regulates the production of the human chemokine CCL3-L1. European Journal of Immunology, 32(10), pp. 3016-3026. (doi: 10.1002/1521-4141(2002010)32:10<3016::AID-IMMU3016>3.0.CO;2-D)

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Genetic variation in the chemokine system is likely to affect responses to infection, and influence the course of autoimmune and inflammatory disease. We and others have shown that the human β-chemokine CCL3-L1, unlike its related non-allelic isoform CCL3, has high affinity for the chemokine receptors D6, CCR3 and CCR5. Moreover, CCL3-L1, but not CCL3, is susceptible to cleavage by CD26, creating a truncated –2 form with enhanced affinity for CCR1 and CCR5. Strong interaction with CCR5 means that CCL3-L1, and particularly its –2 variant, are by far the most potent natural HIV entry inhibitors described to date. Here, using real-time PCR we have shown that CCL3-L1 and a novel CCL4 isoform (termed CCL4-L1) can vary from 1-6 copies per diploid genome (pdg) in Caucasians and are occasionally completely absent. The other isoforms (CCL3 and CCL4) remain at two copies per dpg. Importantly, in a model system of pro-inflammatory chemokine production (LPS-activated monocytes)higher gene copy number correlates with an increased ratio of CCL3-L1 versus CCL3 mRNA, and enhanced chemokine production. Supernatants from samples with high copy number are able to more potently chemoattract CCR5-expressing cells, an effect blocked with anti-CCL3/CCL3-L1 antibodies. As a result of these studies, we hypothesize that genetic variation in CCL3-L1 gene copy number may affect the susceptibility to, or the progression or severity of, diseases in which this chemokine plays a role.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Nibbs, Professor Rob
Authors: Townson, J. R., Barcellos, L. F., and Nibbs, R. J.B.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:European Journal of Immunology
Journal Abbr.:Eur. J. Immunol.
ISSN (Online):1521-4141
Published Online:27 September 2002

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