Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain (original) (raw)

Nature volume 421, pages 744–748 (2003)Cite this article

Abstract

Interleukin-12 (IL-12) is a heterodimeric molecule composed of p35 and p40 subunits. Analyses in vitro have defined IL-12 as an important factor for the differentiation of naive T cells into T-helper type 1 CD4+ lymphocytes secreting interferon-γ (refs 1, 2). Similarly, numerous studies3,4,5,6,7 have concluded that IL-12 is essential for T-cell-dependent immune and inflammatory responses in vivo, primarily through the use of IL-12 p40 gene-targeted mice and neutralizing antibodies against p40. The cytokine IL-23, which comprises the p40 subunit of IL-12 but a different p19 subunit8, is produced predominantly by macrophages and dendritic cells, and shows activity on memory T cells. Evidence from studies of IL-23 receptor expression9 and IL-23 overexpression in transgenic mice10 suggest, however, that IL-23 may also affect macrophage function directly. Here we show, by using gene-targeted mice lacking only IL-23 and cytokine replacement studies, that the perceived central role for IL-12 in autoimmune inflammation, specifically in the brain, has been misinterpreted and that IL-23, and not IL-12, is the critical factor in this response. In addition, we show that IL-23, unlike IL-12, acts more broadly as an end-stage effector cytokine through direct actions on macrophages.

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Acknowledgements

We thank J. Cupp and the DNAX FACS Facility; and K. Moore, G. Zurawski and D. Rennick for comments. DNAX Research Inc. is supported by Schering-Plough.

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Author notes

  1. Sergio A. Lira
    Present address: Immunobiology Center, Mount Sinai School of Medicine, New York, New York, 10029-6574, USA

Authors and Affiliations

  1. Department of Immunology, DNAX Research Inc., Palo Alto, California, 94304-1104, USA
    Daniel J. Cua, Jonathan Sherlock, Yi Chen, Craig A. Murphy, Barbara Joyce, Brian Seymour, Linda Lucian & Jonathon D. Sedgwick
  2. Department of Genomics, DNAX Research Inc., Palo Alto, California, 94304-1104, USA
    Daniel Gorman & Robert A. Kastelein
  3. Department of Protein and Antibody Technology, DNAX Research Inc., Palo Alto, California, 94304-1104, USA
    Wayne To, Sylvia Kwan, Tatyana Churakova & Sandra Zurawski
  4. Department of Immunology, Schering-Plough Research Institute, Kenilworth, New Jersey, 07033, USA
    Maria Wiekowski & Sergio A. Lira

Authors

  1. Daniel J. Cua
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  2. Jonathan Sherlock
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  3. Yi Chen
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  5. Barbara Joyce
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  7. Linda Lucian
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  10. Tatyana Churakova
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  11. Sandra Zurawski
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  12. Maria Wiekowski
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  13. Sergio A. Lira
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  14. Daniel Gorman
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Correspondence toDaniel J. Cua.

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Cua, D., Sherlock, J., Chen, Y. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.Nature 421, 744–748 (2003). https://doi.org/10.1038/nature01355

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