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


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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Figure 1: Generation of IL-23-deficient mice.
Figure 2: IL-23, and not IL-12, is required for the induction of EAE.
Figure 3: TH1 cells are induced in p19-/- but not p35-/- mice.
Figure 4: TH1 cells and inflammatory macrophages enter the CNS of MOG-immunized p19-/- mice but fail to induce EAE.
Figure 5: IL-23, and not IL-12, induces IL-1β and TNF mRNA expression in macrophages.

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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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Correspondence to Daniel 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).

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