Uncoupling of inflammatory chemokine receptors by IL-10: generation of functional decoys

Abstract

As originally demonstrated for the interleukin 1 (IL-1) type II receptor, some primary proinflammatory cytokines from the IL-1 and tumor necrosis factor families are regulated by decoy receptors that are structurally incapable of signaling. Here we report that concomitant exposure to proinflammatory signals and IL-10 generates functional decoy receptors in the chemokine system. Inflammatory signals, which cause dendritic cell (DC) maturation and migration to lymphoid organs, induce a chemokine receptor switch, with down-regulation of inflammatory receptors (such as CCR1, CCR2, CCR5) and induction of CCR7. Concomitant exposure to lipopolysaccharide (LPS) and IL-10 blocks the chemokine receptor switch associated with DC maturation. LPS + IL-10-treated DCs showed low expression of CCR7 and high expression of CCR1, CCR2 and CCR5. These receptors were unable to elicit migration. We provide evidence that uncoupled receptors, expressed on LPS + IL-10-treated cells, sequester and scavenge inflammatory chemokines. Similar results were obtained for monocytes exposed to activating signals and IL-10. Thus, in an inflammatory environment, IL-10 generates functional decoy receptors on DC and monocytes, which act as molecular sinks and scavengers for inflammatory chemokines.

Involvement of leptin signaling in the survival and maturation of bone marrow‐derived dendritic cells

“…IL-10 was previously shown to impact DC migration negatively in vivo through its specific down-regulation of CCR-7 expression [41]. A study by D'Amico et al revealed that concomitant exposure to IL-10 completely blocks the LPS-induced chemokine receptor switch associated with DC maturation [35]. Therefore, the up-regulated production of IL-10 by db/db DC may contribute to the observed alteration in chemokine receptor expression.…”

“…There is compelling evidence that IL-12 production is also affected by cross-regulation between different DC subsets, involving cytokines such as IL-10 and type I IFN [34,35]. Thus, the marked reduction of IL-12p70 secretion by db/db DC may result from increased IL-10 expression.…”

Expression profiling of IL‐10‐regulated genes in human monocytes and peripheral blood mononuclear cells from psoriatic patients during IL‐10 therapy

“…Despite the downregulation of CCR5 ligands, the receptor itself is upregulated in vitro and in vivo. A possible explanation for these contradictory results might be the recent observation, that these up-regulated receptors have only a scavenging effect but are unable to signal [20]. Noticeably, there is a strong down-regulation of the CCR6 ligand CCL20 (Exodus), a chemokine which has been observed to be up-regulated in psoriasis [21].…”

The chemokine system: tuning and shaping by regulation of receptor expression and coupling in polarized responses

“…The significance of this observation may in fact relate to the effect of this cytokine when combined with primary proinflammatory signals (34). It was observed that IL-10 blocks down-regulation of inflammatory chemokine receptors induced by LPS alone or in combination with IFN-c in monocytes and dendritic cells.…”