Article | Published:

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

Nature Immunology volume 1, pages 387391 (2000) | Download Citation

Subjects

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4. Science 261, 472– 475 (1993).

  2. 2.

    et al. The type II “receptor” as a decoy target for IL-1 in polymorphonuclear leukocytes: characterization of induction by dexamethasone and ligand binding properties of the released decoy receptor. J. Exp. Med. 179, 739–743 (1994).

  3. 3.

    et al. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature 396, 699– 703 (1998).

  4. 4.

    et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277, 818– 821 (1997).

  5. 5.

    et al. Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. Immunity 10, 127– 136 (1999).

  6. 6.

    et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165–176 (1998).

  7. 7.

    et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89, 309 –319 (1997).

  8. 8.

    , & A membrane-bound Fas decoy receptor expressed by human thymocytes. J. Biol. Chem. 275, 7988– 7933 (2000).

  9. 9.

    The chemokine system: redundancy for robust outputs. Immunol. Today 20, 254–257 ( 1999).

  10. 10.

    Chemokines. Blood 90, 909– 928 (1997).

  11. 11.

    & Chemokines: a new classification system and their role in immunity. Immunity 12, 121–127 (2000).

  12. 12.

    et al. The Duffy antigen receptor for chemokines: Structural analysis and expression in the brain. J. Leuko. Biol. 59, 29–38 (1996).

  13. 13.

    , , , & Cloning and characterization of a novel promiscuous human β-chemokine receptor D6. J. Biol. Chem. 272, 32078–32083 ( 1997).

  14. 14.

    et al. Granulocyte-colony stimulating factor and lipopolysaccharide regulate the expression of interleukin 8 receptors on polymorphonuclear leukocytes . J. Biol. Chem. 270, 28188– 28192 (1995).

  15. 15.

    et al. Bacterial lipopolysaccharide rapidly inhibits expression of C-C chemokine receptors in human monocytes. J. Exp. Med. 185, 969–974 (1997).

  16. 16.

    et al. Interleukin-10 increases CCR5 expression and HIV infection in human monocytes. J. Exp. Med. 187, 439 –444 (1998).

  17. 17.

    et al. Selective inhibition of expression of the chemokine receptor CCR2 in human monocytes by IFN-γ. J. Immunol. 160, 3869–3873 (1998).

  18. 18.

    & Dendritic cells and the control of immunity. Nature 392, 245– 252 (1998).

  19. 19.

    New insights into the mobilization and phagocytic activity of dendritic cells . J. Exp. Med. 183, 1287– 1292 (1996).

  20. 20.

    Chemokines and the homing of dendritic cells to the T cell areas of lymphoid organs. J. Exp. Med. 189, 447– 450 (1999).

  21. 21.

    & Mobilizing dendritic cells for tolerance, priming, and chronic inflammation. J. Exp. Med. 189, 611–614 ( 1999).

  22. 22.

    et al. Migration of dendritic cells in response to formyl peptides, C5a and a distinct set of chemokines. J. Immunol. 155 , 3292–3295 (1995).

  23. 23.

    , , , & Human recombinant monocyte chemotactic protein and other C-C chemokines bind and induce directional migration of dendritic cells in vitro. J. Leuko. Biol. 60 , 365–371 (1996).

  24. 24.

    , , , & The chemokine receptor switch paradigm and dendritic cell migration: its significance in tumor tissues. Immunol. Rev. (in the press, 2000).

  25. 25.

    et al. Cutting edge: Differential regulation of chemokine receptors during dendritic cell maturation: A model for their trafficking properties . J. Immunol. 161, 1083– 1086 (1998).

  26. 26.

    et al. Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur. J. Immunol. 28, 2760–2769 (1998).

  27. 27.

    et al. Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J. Exp. Med. 188, 373–386 (1998).

  28. 28.

    & Biological properties of interleukin 10. Immunol. Today 13, 198– 200 (1992).

  29. 29.

    et al. Interleukin-10 prevents the generation of dendritic cells from human peripheral blood mononuclear cells cultured with Interleukin-4 and granulocyte/macrophage-colony-stimulating factor.. Eur. J. Immunol. 27, 756–762 ( 1997).

  30. 30.

    et al. Interleukin-10 prevents the differentation of monocytes to dendritic cells but promotes their maturation to macrophages. Eur. J. Immunol. 28, 359–369 (1998).

  31. 31.

    et al. Central role for G protein coupled phosphoinositide 3-kinase γ in inflammation. Science 287, 1049– 1053 (2000).

  32. 32.

    et al. Function of PI3Kγ in thymocyte development, T cell activation, and neutrophil migration. Science 287, 1040 –1046 (2000).

  33. 33.

    et al. Roles of PLC-β2 and β3 and PI3Kγ in chemoattractant-mediated signal transduction. Science 287, 1046– 1049 (2000).

  34. 34.

    , , & Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: Downregulation by cytokines and bacterial products. J. Exp. Med. 182 , 389–400 (1995).

  35. 35.

    et al. Potent HIV inhibition of HIV infectivity in macrophages and lymphocytes by a novel CCR5 antagonist. Science 276 , 276–279 (1997).

  36. 36.

    et al. Aminooxypentane-RANTES induces CCR5 internalization but inhibits recycling: A novel inhibitory mechanism of HIV infectivity. J. Exp. Med. 187, 1215–1224 (1998).

  37. 37.

    et al. Differential activation of CC chemokine receptors by AOP-RANTES . J. Biol. Chem. 275, 7787– 7794 (2000).

  38. 38.

    et al. Differential responsiveness to constitutive versus inflammatory chemokines of immature and mature mouse dendritic cells. J. Leuko. Biol. 66, 489–494 ( 1999).

  39. 39.

    , , & The type II 'decoy' receptor: novel regulatory pathway for interleukin-1. Immunol. Today 15, 562–566 (1994).

  40. 40.

    & Death receptors: signaling and modulation. Science 281, 1305– 1308 (1998).

  41. 41.

    & Human cytomegalovirus open reading frame US28 encodes a functional beta chemokine receptor. J. Biol. Chem. 269, 28539–28542 ( 1994).

  42. 42.

    et al. Chemokine sequestration by viral chemoreceptors as a novel viral escape strategy: Withdrawal of chemokines from the environment of cytomegalovirus-infected cells. J. Exp. Med. 188, 855– 866 (1998).

  43. 43.

    et al. Receptor expression and responsiveness of human dendritic cells to a defined set of CC and CXC chemokines. J. Immunol. 159, 1993–2000 (1997).

  44. 44.

    et al. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 6, 315 –325 (1997).

  45. 45.

    , , & A simple method for evaluating the rejection of grafted spleen cells by flow cytometry and tracing adoptively transferred cells by light microscopy. J. Immunol. Meth. 207, 33–42 (1997).

  46. 46.

    , , & Three populations of mouse lymph node dendritic cells with different origins and dynamics. J. Immunol. 160, 708– 717 (1998).

Download references

Acknowledgements

Supported by the Italian Association for Cancer Research (AIRC), National Research Council (CNR) Target Project Biotechnology, Special project AIDS (40B.63 and 30B.87) of Istituto Superiore di Sanità and European Community Project BMH4-CT98-2343. We thank F. and V. De Ceglie for the artwork.

Author information

Affiliations

  1. Department of Immunology and Cell Biology, Istituto di Ricerche Farmacologiche 'Mario Negri', Via Eritrea 62, 20157 Milano, Italy.

    • G. D'Amico
    • , G. Frascaroli
    • , G. Bianchi
    • , P. Transidico
    • , A. Doni
    • , A. Vecchi
    • , S. Sozzani
    • , P. Allavena
    •  & A. Mantovani
  2. Institute of General Pathology, University of Milano, Via Mangiagalli, 31, 20100, Milano, Italy.

    • A. Mantovani

Authors

  1. Search for G. D'Amico in:

  2. Search for G. Frascaroli in:

  3. Search for G. Bianchi in:

  4. Search for P. Transidico in:

  5. Search for A. Doni in:

  6. Search for A. Vecchi in:

  7. Search for S. Sozzani in:

  8. Search for P. Allavena in:

  9. Search for A. Mantovani in:

Corresponding author

Correspondence to A. Mantovani.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/80819

Further reading