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

Nature. 2003 Feb 13;421(6924):744-8. doi: 10.1038/nature01355.

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-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmune Diseases of the Nervous System / genetics
  • Autoimmune Diseases of the Nervous System / immunology*
  • Autoimmune Diseases of the Nervous System / pathology*
  • Brain / immunology*
  • Brain / pathology*
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Gene Deletion
  • Gene Expression Regulation
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / pathology
  • Interleukin-1 / genetics
  • Interleukin-12 / chemistry
  • Interleukin-12 / genetics
  • Interleukin-12 / immunology*
  • Interleukin-23
  • Interleukin-23 Subunit p19
  • Interleukins / chemistry
  • Interleukins / genetics
  • Interleukins / immunology*
  • Macrophages / immunology
  • Mice
  • Mice, Knockout
  • Protein Subunits / chemistry
  • Protein Subunits / genetics
  • Protein Subunits / immunology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Th1 Cells / immunology*
  • Tumor Necrosis Factor-alpha / genetics

Substances

  • Il23a protein, mouse
  • Interleukin-1
  • Interleukin-23
  • Interleukin-23 Subunit p19
  • Interleukins
  • Protein Subunits
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Interleukin-12