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Nature 421, 744-748 (13 February 2003) | doi:10.1038/nature01355; Received 10 September 2002; Accepted 14 November 2002

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

Daniel J. Cua1, Jonathan Sherlock1, Yi Chen1, Craig A. Murphy1, Barbara Joyce1, Brian Seymour1, Linda Lucian1, Wayne To2, Sylvia Kwan2, Tatyana Churakova2, Sandra Zurawski2, Maria Wiekowski3, Sergio A. Lira3,4, Daniel Gorman5, Robert A. Kastelein5 & Jonathon D. Sedgwick1

  1. Department of Immunology, DNAX Research Inc., Palo Alto, California 94304-1104, USA
  2. Department of Genomics, DNAX Research Inc., Palo Alto, California 94304-1104, USA
  3. Department of Protein and Antibody Technology, DNAX Research Inc., Palo Alto, California 94304-1104, USA
  4. Department of Immunology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
  5. Present address: Immunobiology Center, Mount Sinai School of Medicine, New York, New York 10029-6574, USA

Correspondence to: Daniel J. Cua1 Correspondence and requests for materials should be addressed to D.J.C. (e-mail: Email: daniel.cua@dnax.org).

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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-gamma (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.

  1. Department of Immunology, DNAX Research Inc., Palo Alto, California 94304-1104, USA
  2. Department of Genomics, DNAX Research Inc., Palo Alto, California 94304-1104, USA
  3. Department of Protein and Antibody Technology, DNAX Research Inc., Palo Alto, California 94304-1104, USA
  4. Department of Immunology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
  5. Present address: Immunobiology Center, Mount Sinai School of Medicine, New York, New York 10029-6574, USA

Correspondence to: Daniel J. Cua1 Correspondence and requests for materials should be addressed to D.J.C. (e-mail: Email: daniel.cua@dnax.org).