Cutting edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis.
Although IL-12 and IL-23 share the common p40 subunit, IL-23, rather than IL-12, seems to drive the pathogenesis of experimental autoimmune encephalomyelitis and arthritis, because IL-23/p19 knockout mice are protected from disease. In contrast, we describe in this study that newly created LacZ knockin mice deficient for IL-23 p19 were highly susceptible for the development of experimental T cell-mediated TNBS colitis and showed even more severe colitis than wild-type mice by endoscopic and histologic criteria. Subsequent studies revealed that dendritic cells from p19-deficient mice produce elevated levels of IL-12, and that IL-23 down-regulates IL-12 expression upon TLR ligation. Finally, in vivo blockade of IL-12 p40 in IL-23-deficient mice rescued mice from lethal colitis. Taken together, our data identify cross-regulation of IL-12 expression by IL-23 as novel key regulatory pathway during initiation of T cell dependent colitis.
Becker
Christoph
C
Laboratory of Immunology, First Medical Clinic, University of Mainz, Mainz, Germany.
Dornhoff
Heike
H
Neufert
Clemens
C
Fantini
Massimo C
MC
Wirtz
Stefan
S
Huebner
Sabine
S
Nikolaev
Alexei
A
Lehr
Hans-Anton
HA
Murphy
Andrew J
AJ
Valenzuela
David M
DM
Yancopoulos
George D
GD
Galle
Peter R
PR
Karow
Margaret
M
Neurath
Markus F
MF
D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D015536:Down-Regulation; D018664:Interleukin-12 / Q000096:biosynthesis*; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D013601:T-Lymphocytes / Q000378:metabolism*
C508841:Il23a protein, mouse; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D021122:Protein Subunits; D018664:Interleukin-12