Uncoupling of inflammatory chemokine receptors by IL-10: generation of functional decoys.
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.
D'Amico
G
G
Department of Immunology and Cell Biology, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milano, Italy.
Frascaroli
G
G
Bianchi
G
G
Transidico
P
P
Doni
A
A
Vecchi
A
A
Sozzani
S
S
Allavena
P
P
Mantovani
A
A
D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism*; D016753:Interleukin-10 / Q000494:pharmacology*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D019707:Receptors, Chemokine / Q000378:metabolism*
D018836:Inflammation Mediators; D008024:Ligands; D008070:Lipopolysaccharides; D019707:Receptors, Chemokine; D016753:Interleukin-10