Synergistic up-regulation of MCP-2/CCL8 activity is counteracted by chemokine cleavage, limiting its inflammatory and anti-tumoral effects

Sofie Struyf, Paul Proost, Jo Vandercappellen, Sebastian Dempe, Becky Noyens, Sofie Nelissen, Meike Gouwy, Massimo Locati, Ghislain Opdenakker, Christine Dinsart, Jo Van Damme

Research output: Contribution to journalArticlepeer-review

Abstract

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-1β or IFN-γ, unless these cytokineswere combined. IFN-γ 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 NH2-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 antitumoral potential.

Original languageEnglish
Pages (from-to)843-857
Number of pages15
JournalEuropean Journal of Immunology
Volume39
Issue number3
DOIs
Publication statusPublished - 2009

Keywords

  • Cell migration
  • Chemokines
  • Inflammation
  • Tumor immunology

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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