CCL5, also known as RANTES (Regulated upon Activation, Normal T cell Expressed and presumably Secreted), is an 8 kDa beta -chemokine that plays a primary role in the inflammatory immune response by means of its ability to attract and activate leukocytes [1- 3]. Human and mouse RANTES exhibit cross-species activity on human and mouse cells [4]. Mature mouse CCL5 shares 100% aa sequence identity with rat CCL5 and 75% - 88% with canine, cotton rat, feline, and human CCL5 [5]. CCL5 is secreted by many cell types at inflammatory sites, and it exerts a wide range of activities through the receptors CCR1, CCR3, CCR4, and CCR5 [6, 7]. Inflammatory responses can be impaired by the sequestration of CCL5 by the cytomegalovirus protein US28 [8]. In humans, CCR5 binding to CCL5 inhibits the infectivity of R5 (M-tropic) but not X4 (T-tropic) strains of HIV-1 [9]. The two N-terminal residues of CCL5 can be removed by CD26/DPPIV, generating a protein that functions as a chemotaxis inhibitor and more effectively blocks M-tropic HIV-1 infection of monocytes [10]. Oligomerization of CCL5 on glycosaminoglycans is required for CCR1-mediated leukocyte adhesion and activation as well as CCL5’s interaction with the chemokine CXCL4/PF4 [11-13]. The deposition of CCL5 on activated vascular endothelial cells is crucial for monocyte adhesion to damaged vasculature, but CCL5 oligomerization is not required for the extravasation of adherent leukocytes [14-16]. CCL5 is upregulated in breast cancer and promotes tumor progression through the attraction of proinflammatory macrophages in addition to its actions on tumor cells, stromal cells, and the vasculature [17].
Reference
[1] Schall, T.J. et al. (1990) Nature 347:669.
[2] Bacon, K.B. et al. (1995) Science 269:1727.
[3] Fischer, F.R. et al. (2001) J. Immunol. 167:1637.
[4] Schall, T.J. et al. (1992) Eur. J. Immunol. 22:1477.
[5] Heeger, P. et al. (1992) Kidney Int. 41:220.
[6] Appay, V. and S.L. Rowland-Jones (2001) Trends Immunol. 22:83.
[7] Levy, J.A. (2009) J. Immunol. 182:3945.
[8] Randolph-Habecker, J.R. et al. (2002) Cytokine 19:37.
[9] DeVico, A.L. and Gallo, R.C. (2004) Nat. Rev. Microbiol. 2:401.
[10] Proost, P. et al. (1998) J. Biol. Chem. 273:7222.
[11] Appay, V. et al. (1999) J. Biol. Chem. 274:27505.
[12] Proudfoot, A.E.I. et al. (2003) Proc. Natl. Acad. Sci. 100:1885.
[13] von Hundelshausen, P. et al. (2005) Blood 105:924.
[14] von Hundelshausen, P. et al. (2001) Circulation 103:1772.
[15] Zernecke, A. et al. (2008) Arterioscler. Thromb. Vasc. Biol. 28:1897.
[16] Baltus, T. et al. (2003) Blood 102:1985.
[17] Soria, G. and A. Ben-Baruch (2008) Cancer Lett. 267:271