Synergistic up-regulation of MCP-2/CCL8 activity is counteracted by chemokine cleavage, limiting its inflammatory and anti-tumoral effects.
Chemokines mediate the inflammatory response by attracting various leukocyte types. MCP-2/CC chemokine ligand 8 (CCL8) was induced at only suboptimal levels in fibroblasts and endothelial cells by IL-1beta or IFN-gamma, unless these cytokines were combined. IFN-gamma also synergized with the TLR ligands peptidoglycan (TLR2), dsRNA (TLR3) or LPS (TLR4). Under these conditions, intact MCP-2/CCL8(1-76) produced by fibroblasts was found to be processed into MCP-2/CCL8(6-75), which lacked chemotactic activity for monocytic cells. Furthermore, the capacity of MCP-2/CCL8(6-75) to increase intracellular calcium levels through CCR1, CCR2, CCR3 and CCR5 was severely reduced. However, the truncated isoform still blocked these receptors for other ligands. MCP-2/CCL8(6-75) induced internalization of CCR2, inhibited MCP-1/CCL2 and MCP-2/CCL8 ERK signaling and antagonized the chemotactic activity of several CCR2 ligands (MCP-1/CCL2, MCP-2/CCL8, MCP-3/CCL7). In contrast to MCP-3/CCL7, parvoviral delivery of MCP-2/CCL8 into B78/H1 melanoma failed to inhibit tumor growth, partially due to proteolytic cleavage into inactive MCP-2/CCL8 missing five NH(2)-terminal residues. However, in an alternative tumor model, using HeLa cells, MCP-2/CCL8 retarded tumor development. These data indicate that optimal induction and delivery of MCP-2/CCL8 is counteracted by converting this chemokine into a receptor antagonist, thereby losing its anti-tumoral potential.
Struyf
Sofie
S
Laboratory of Molecular Immunology, Rega Institute for Medical Research, K.U. Leuven, Leuven, Belgium.
Proost
Paul
P
Vandercappellen
Jo
J
Dempe
Sebastian
S
Noyens
Becky
B
Nelissen
Sofie
S
Gouwy
Mieke
M
Locati
Massimo
M
Opdenakker
Ghislain
G
Dinsart
Christiane
C
Van Damme
Jo
J
D000818:Animals; D002118:Calcium / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000276:immunology / Q000378:metabolism; D054412:Chemokine CCL8 / Q000276:immunology / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000032:analysis; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D009369:Neoplasms / Q000276:immunology*; D010457:Peptidoglycan / Q000494:pharmacology; D019707:Receptors, Chemokine / Q000276:immunology* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
C111835:CCL2 protein, human; C515453:CCL8 protein, human; D018932:Chemokine CCL2; D054412:Chemokine CCL8; D017077:Culture Media, Conditioned; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D010457:Peptidoglycan; D019707:Receptors, Chemokine; D051193:Toll-Like Receptors; D007371:Interferon-gamma; D002118:Calcium