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JOURNAL ARTICLE

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

Daniel J Cua, Jonathan Sherlock, Yi Chen, Craig A Murphy, Barbara Joyce, Brian Seymour, Linda Lucian, Wayne To, Sylvia Kwan, Tatyana Churakova, Sandra Zurawski, Maria Wiekowski, Sergio A Lira, Daniel Gorman, Robert A Kastelein, Jonathon D Sedgwick
Nature 2003 February 13, 421 (6924): 744-8
12610626
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 studies 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 subunit, is produced predominantly by macrophages and dendritic cells, and shows activity on memory T cells. Evidence from studies of IL-23 receptor expression and IL-23 overexpression in transgenic mice 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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