Letter | Published:

Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation

Nature volume 387, pages 611617 (05 June 1997) | Download Citation

Subjects

  • An Erratum to this article was published on 04 September 1997

Abstract

Chemokines are small secreted proteins that stimulate the directional migration of leukocytes and mediate inflammation1,2,3,4. During screening of a murine choroid plexus complementary DNA library, we identified a new chemokine, designated neurotactin. Unlike other chemokines, neurotactin has a unique cysteine pattern, Cys-X-X-X-Cys, and is predicted to be a type 1 membrane protein. Full-length recombinant neurotactin is localized on the surface of transfected 293 cells. Recombinant neurotactin containing the chemokine domain is chemotactic for neutrophils both in vitro and in vivo. Neurotactin messenger RNA is predominantly expressed in normal murine brain and its protein expression in activated brain microglia is upregulated in mice with experimental autoimmune encephalomyelitis, as well as in mice treated with lipopolysaccharide. Distinct from all other chemokine genes, the neurotactin gene is localized to human chromosome 16q. Consequently we propose that neurotactin represents a new δ-chemokine family and that it may play a role in brain inflammation processes.

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.

    , , & Properties of the novel proinflammatory supergene “intercrine” cytokine family. Annu. Rev. Immunol. 9, 617–648 (1991).

  2. 2.

    & CC chemokines in allergic inflammation Immunol. Today 15, 127–133 (1994).

  3. 3.

    , & Interleukin-8 and related chemotactic cytokines-CXC and CC chemokines. Adv. Immunol. 55, 97–197 (1994).

  4. 4.

    & Chemokines, leukocyte trafficking, and inflammation. Curr. Opin. Immunol. 6, 865–873 (1994).

  5. 5.

    et al. Lymphotactin: a cytokine that represents a new class of chemokine Science 266, 1395–1399 (1994).

  6. 6.

    et al. Molecular cloning and functional characterization of human lymphotactin. J. Immunol. 155, 203–209 (1995).

  7. 7.

    , , , & Molecular cloning of a novel C or g type chemokine, SCM-1. FEBS Lett. 360, 155–159 (1995).

  8. 8.

    et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263–1271 (1995).

  9. 9.

    , , & Neutrophil-activating properties of the melanoma growth-stimulatory activity. J. Exp. Med. 171, 1797–1802 (1990).

  10. 10.

    , & Microglia: intrinsic immunoeffector cell of the brain. Brain Res. Rev. 20, 269–278 (1995).

  11. 11.

    , , & High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient auto-myelin basic protein T cell receptor transgenic mice. Cell 78, 399–408 (1994).

  12. 12.

    & Differential binding of chemokines to glycosaminoglycan subpopulations. Curr. Biol. 4, 394–400 (1994).

  13. 13.

    & Membrane-anchored growth factors. Annu. Rev. Biochem. 62, 515–541 (1993).

  14. 14.

    , & Transmembrane form of the kit ligand growth factor is determined by alternative splicing and is missing in the Sld mutant. Cell 64, 1025–1035 (1991).

  15. 15.

    et al. Steel-Dickie mutation encodes a c-kit ligand lacking transmembrane and cytoplasmic domains. Proc. Natl Acad. Sci. USA 88, 4671–4674 (1991).

  16. 16.

    et al. Crystal structure of interleukin 8: symbiosis of NMR and crystallography. Proc. Natl Acad. Sci. USA 88, 502–506 (1991).

  17. 17.

    , & Scanning mutagenesis of interleukin-8 identifies a cluster of residues required for receptor binding. J. Biol. Chem. 266, 18989–18994 (1991).

  18. 18.

    , , & Structure-activity relationships of interleukin-8 determined using chemically synthesized analogs. Critical role of NH2-terminal residues and evidence for uncoupling of neutrophil chemotaxis, exocytosis, and receptor binding activities. J. Biol. Chem. 266, 23128–23134 (1991).

  19. 19.

    et al. Arg-X-Lys/Arg-Arg motif as a signal for precursor cleavage catalyzed by furin within the constitutive secretory pathway. J. Biol. Chem. 266, 12127–12130 (1991).

  20. 20.

    , & The cytoplasmic carboxy-terminal amino acid specifies cleage of membrane TGFα into soluble growth factor. Cell 71, 1157–1165 (1992).

  21. 21.

    & Polymorphonuclear leukocytes and monocytes/Macrophages in the pathogenesis of cerebral ischemia and stroke. Stroke 23, 1367–1379 (1992).

  22. 22.

    , , , & Basic local alignment search tool. J. Mol. Biol. 215, 403–410 (1990).

  23. 23.

    & Identification of protein coding regions by database similarity search. Nature Genet. 3, 266–272 (1993).

  24. 24.

    Anew method for predicting signal sequence cleavage sites. Nucleic Acids Res. 14, 4683–4690 (1986).

  25. 25.

    , , & Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry5294–5299 (1979).

  26. 26.

    , & A48-well micro chemotaxis assembly for rapid and accurate measurement of leukocyte migration. J. Immunol. Methods 33, ((1980)).

  27. 27.

    , , , & The neutrophil-activating protein (NAP-1) is also chemotactic for T lymphocytes. Science 243, 1464–1466 (1989).

  28. 28.

    , , , & Higher-affinity oligosaccharide ligands for E-selectin. J. Clin. Invest. 19, 1157–1166 (1993).

  29. 29.

    , , , & Extracellular adenosine triphosphate activates calcium mobilization in human phagocytic leukocytes and neutrophil/monocyte progenitor cells. J. Clin. Invest. 83, 1651–1660 (1989).

  30. 30.

    et al. B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy. Cell 80, 707–718 (1995).

  31. 31.

    et al. Structure and chromosomal localization of the human stromal cell-derived factor 1 (SDF1) gene. Genomics 28, 495–500 (1995).

Download references

Acknowledgements

We thank F. Lee, G. Duyk, B. Tepper, M. P. Das, J. Lafaille, D. Levinson, S. Lin, P.Stroobant, G. Jia, D. Holtzman, S. McCarthy, D. Michnick and S. Busfield for advice and support. We are grateful for the expert technical assistance of the Millennium sequencing and bioinformatics group.

Author information

Affiliations

  1. Millennium Pharmaceuticals Inc., 640 Memorial Drive, Cambridge, Massachusetts 02139, USA

    • Yang Pan
    • , Clare Lloyd
    • , Hong Zhou
    • , Sylvia Dolich
    • , Jim Deeds
    • , Jose-Angel Gonzalo
    • , Jim Vath
    • , Mike Gosselin
    • , Jingya Ma
    • , Barry Dussault
    • , Elizabeth Woolf
    • , Geoff Alperin
    • , Janice Culpepper
    • , Jose Carlos Gutierrez-Ramos
    •  & David Gearing

Authors

  1. Search for Yang Pan in:

  2. Search for Clare Lloyd in:

  3. Search for Hong Zhou in:

  4. Search for Sylvia Dolich in:

  5. Search for Jim Deeds in:

  6. Search for Jose-Angel Gonzalo in:

  7. Search for Jim Vath in:

  8. Search for Mike Gosselin in:

  9. Search for Jingya Ma in:

  10. Search for Barry Dussault in:

  11. Search for Elizabeth Woolf in:

  12. Search for Geoff Alperin in:

  13. Search for Janice Culpepper in:

  14. Search for Jose Carlos Gutierrez-Ramos in:

  15. Search for David Gearing in:

Corresponding author

Correspondence to Yang Pan.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/42491

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.