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

As originally demonstrated for the interleukin I (IL-1) type II receptor, s ome primary proinflammatory cytokines from the IL-1 and tumor necrosis fact or families are regulated by decoy receptors that are structurally incapabl e of signaling. Here we report that concomitant exposure to proinflammatory signals and IL-10 generates functional decoy receptors in the chemokine sy stem. 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 inducti on of CCR7. Concomitant exposure to lipopolysaccharide (LPS) and IL-10 bloc ks the chemokine receptor switch associated with DC maturation. LPS + IL-10 -treated DCs showed low expression of CCR7 and high expression of CCR1, CCR 2 and CCR5. These receptors were unable to elicit migration. We provide evi dence that uncoupled receptors, expressed on LPS + IL-10-treated cells, seq uester and scavenge inflammatory chemokines. Similar results were obtained for monocytes exposed to activating signals and IL-10. Thus, in an inflamma tory environment, IL-10 generates functional decoy receptors on DC and mono cytes, which act as molecular sinks and scavengers for inflammatory chemoki nes.