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-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.
Cua
Daniel J
DJ
Department of Immunology, DNAX Research Inc., Palo Alto, California 94304-1104, USA. daniel.cua@dnax.org
Sherlock
Jonathan
J
Chen
Yi
Y
Murphy
Craig A
CA
Joyce
Barbara
B
Seymour
Brian
B
Lucian
Linda
L
To
Wayne
W
Kwan
Sylvia
S
Churakova
Tatyana
T
Zurawski
Sandra
S
Wiekowski
Maria
M
Lira
Sergio A
SA
Gorman
Daniel
D
Kastelein
Robert A
RA
Sedgwick
Jonathon D
JD
D000818:Animals; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D001921:Brain / Q000276:immunology* / Q000473:pathology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D017353:Gene Deletion; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007375:Interleukin-1 / Q000235:genetics; D018664:Interleukin-12 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
C508841:Il23a protein, mouse; D007375:Interleukin-1; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D021122:Protein Subunits; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12