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Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation

Nature volume 387, pages 611–617 (1997)Cite this article

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.

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Figure 1: Amino-acid sequence alignment of human and murine neurotactin (abbreviated as NTN).
Figure 2: Sequence alignment of human neurotactin with α-chemokines IL-8 and GRO-α; β-chemokines MCP-1 and RANTES and γ-chemokine lymphotactin.
Figure 3: Murine tissue northern blot probed with a full-length murine neurotactin cDNA probe.
Figure 4: Immunofluorescent labelling of transfected 293 cells.
Figure 5: Chemotaxis assay of recombinant murine neurotactin on purified human neutrophils (a), monocytes (b) and lymphocytes (c).
Figure 6: Neutrotactin-induced recruitment of leukocytes to the peritoneum.
Figure 7: Expression of murine neurotactin in normal, LPS-treated and EAE brain.

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References

  1. Oppenheim, J. J., Zachariae, C. O. C., Mukaida, N. & Mursushima, K. Properties of the novel proinflammatory supergene “intercrine” cytokine family. Annu. Rev. Immunol. 9, 617–648 (1991).

    Article  CAS  Google Scholar 

  2. Baggiolini, M. & Dahinden, C. A. CC chemokines in allergic inflammation Immunol. Today 15, 127–133 (1994).

    Article  CAS  Google Scholar 

  3. Baggiolini, M., Dewald, B. & Moser, B. Interleukin-8 and related chemotactic cytokines-CXC and CC chemokines. Adv. Immunol. 55, 97–197 (1994).

    Article  CAS  Google Scholar 

  4. Schall, T. J. & Bacon, K. B. Chemokines, leukocyte trafficking, and inflammation. Curr. Opin. Immunol. 6, 865–873 (1994).

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  7. Yoshida, T., Imai, T., Kakizaki, M., Nishimura, M. & Yoshie, O. Molecular cloning of a novel C or g type chemokine, SCM-1. FEBS Lett. 360, 155–159 (1995).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. Moser, B., Clark-Lewis, I., Awahlen, R. & Baggiolini, M. Neutrophil-activating properties of the melanoma growth-stimulatory activity. J. Exp. Med. 171, 1797–1802 (1990).

    Article  CAS  Google Scholar 

  10. Gehrmann, J., Matsumoto, Y. & Kreutxberg, G. W. Microglia: intrinsic immunoeffector cell of the brain. Brain Res. Rev. 20, 269–278 (1995).

    Article  CAS  Google Scholar 

  11. Lafaille, J. J., Nagashima, K., Katsuki, M. & Tonegawa, A. High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient auto-myelin basic protein T cell receptor transgenic mice. Cell 78, 399–408 (1994).

    Article  CAS  Google Scholar 

  12. Witt, D. P. & Lander, A. D. Differential binding of chemokines to glycosaminoglycan subpopulations. Curr. Biol. 4, 394–400 (1994).

    Article  CAS  Google Scholar 

  13. Massague, J. & Pandiella, A. Membrane-anchored growth factors. Annu. Rev. Biochem. 62, 515–541 (1993).

    Article  CAS  Google Scholar 

  14. Flanagan, J. G., Chan, D. C. & Leder, P. 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).

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  17. Hebert, C. A., Vitangcol, R. V. & Baker, J. B. Scanning mutagenesis of interleukin-8 identifies a cluster of residues required for receptor binding. J. Biol. Chem. 266, 18989–18994 (1991).

    CAS  PubMed  Google Scholar 

  18. Clark-Lewis, I., Schumacher, C., Baggiolini, M. & Moser, B. 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).

    CAS  PubMed  Google Scholar 

  19. Hosaka, M. 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).

    CAS  PubMed  Google Scholar 

  20. Bosenberg, M., Pandiella, A. & Massague, J. The cytoplasmic carboxy-terminal amino acid specifies cleage of membrane TGFα into soluble growth factor. Cell 71, 1157–1165 (1992).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Altschul, S. F., Gish, W., Miller, W., Myers, E. W. & Lipman, D. J. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 (1990).

    Article  CAS  Google Scholar 

  23. Gish, W. & States, D. J. Identification of protein coding regions by database similarity search. Nature Genet. 3, 266–272 (1993).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. Chirgwin, J. M., Przbyla, A. E., MacDonald, R. J. & Rutter, W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 5294–5299 (1979).

  26. Falk, W., Goodwin, R. H. J. & Leonard, E. J. A48-well micro chemotaxis assembly for rapid and accurate measurement of leukocyte migration. J. Immunol. Methods 33, ((1980)).

  27. Larson, C. G., Anderson, A. O., Appella, E., Oppenheim, J. J. & Matsushima, K. The neutrophil-activating protein (NAP-1) is also chemotactic for T lymphocytes. Science 243, 1464–1466 (1989).

    Article  ADS  Google Scholar 

  28. Nelson, R. M., Dolich, S., Aruffo, A., Cecconi, O. & Devilacqua, M. P. Higher-affinity oligosaccharide ligands for E-selectin. J. Clin. Invest. 19, 1157–1166 (1993).

    Article  Google Scholar 

  29. Cowen, D. S., Lazarus, H. M., Shurin, S. B., Stoll, S. E. & Dubyak, G. R. Extracellular adenosine triphosphate activates calcium mobilization in human phagocytic leukocytes and neutrophil/monocyte progenitor cells. J. Clin. Invest. 83, 1651–1660 (1989).

    Article  CAS  Google Scholar 

  30. Kuchroo, V. K. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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.

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

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Correspondence to Yang Pan.

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Pan, Y., Lloyd, C., Zhou, H. et al. Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation. Nature 387, 611–617 (1997). https://doi.org/10.1038/42491

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