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)

Full text not currently available from Enlighten.

Publisher's URL: http://dx.doi.org/10.1002/1521-4141(2002010)32:10<3016::AID-IMMU3016>3.0.CO;2-D

Abstract

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
Status:Published
Refereed:Yes
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:0014-2980
ISSN (Online):1521-4141
Published Online:27 September 2002

University Staff: Request a correction | Enlighten Editors: Update this record