Deletion of interleukin-12p40 suppresses autoimmune cholangitis in dominant negative transforming growth factor beta receptor type II mice.
Our laboratory has reported that mice that express a dominant negative form of transforming growth factor beta receptor restricted to T cells (dnTGFbetaRII) develop an inflammatory biliary ductular disease with elevated serum levels of interleukin (IL)-12p40 and other proinflammatory cytokines and antimitochondrial autoantibodies (AMAs) closely resembling human primary biliary cirrhosis (PBC). We have used this mouse model to address the potential mechanisms of immunomodulation of liver disease by creating two unique genetic strains: IL-12p40 knockout (KO)-dnTGFbetaRII mice and IFN-gamma KO-dnTGFbetaRII mice. The two colonies of genetically modified mice-and, for purposes of controls, the dnTGFbetaRII mice-were monitored for liver immunopathology, AMAs, and intrahepatic cytokine production. Disease expression in the IFN-gamma KO-dnTGFbetaRII mice, including liver immunopathology, were similar to those of dnTGFbetaRII mice, whereas the IL-12p40 KO-dnTGFbetaRII mice had a dramatic reduction in histological autoimmune cholangitis and significant decreases in levels of intrahepatic proinflammatory cytokines, but similar levels of AMAs compared with dnTGFbetaRII controls.


CONCLUSIONS
These data indicate that in this mouse model of PBC, signaling by way of IL-12p40 is an essential requirement for the development of autoimmune cholangitis. The results of these studies will play an important role in identifying pathways and reagents that will selectively inhibit IL-12 signaling for the outlining of future therapeutic strategies for human PBC.
Yoshida
Katsunori
K
Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA 95616, USA.
Yang
Guo-Xiang
GX
Zhang
Weici
W
Tsuda
Masanobu
M
Tsuneyama
Koichi
K
Moritoki
Yuki
Y
Ansari
Aftab A
AA
Okazaki
Kazuichi
K
Lian
Zhe-Xiong
ZX
Coppel
Ross L
RL
Mackay
Ian R
IR
Gershwin
M Eric
ME
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D002761:Cholangitis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000235:genetics* / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
J Immunol. 2001 Nov 1;167(9):5464-9
11673566
J Immunol. 1987 May 15;138(10):3525-31
3571977
J Exp Med. 2005 Jan 17;201(2):233-40
15657292
Immunity. 2000 Nov;13(5):715-25
11114383
J Immunol. 2006 Aug 1;177(3):1655-60
16849474
EMBO Rep. 2004 Feb;5(2):172-7
14749721
J Immunol. 1995 May 15;154(10):5071-9
7730613
Lupus. 2002;11(6):384-7
12139377
J Immunol. 2000 Jun 15;164(12):6495-502
10843707
J Autoimmun. 2008 Nov;31(3):274-80
18501559
Gastroenterology. 2003 Nov;125(5):1379-87
14598254
J Clin Invest. 2002 May;109(9):1231-40
11994412
Eur J Immunol. 1995 Jan;25(1):200-6
7843232
Gastroenterology. 2006 Aug;131(2):606-18
16890612
Gastroenterology. 1997 Apr;112(4):1169-78
9098000
J Immunol. 1999 Jun 1;162(11):6770-5
10352297
J Immunol. 2001 Jul 15;167(2):779-86
11441083
J Leukoc Biol. 2002 Apr;71(4):669-76
11927654
Hepatology. 1996 Mar;23(3):436-44
8617422
Blood. 2001 Feb 1;97(3):601-7
11157474
Hepatology. 2008 Jun;47(6):1974-82
18452147
J Autoimmun. 2008 Sep;31(2):175-9
18707846
Eur J Immunol. 2002 Feb;32(2):541-51
11828371
Immunity. 1996 May;4(5):471-81
8630732
Nature. 2003 Feb 13;421(6924):744-8
12610626
J Exp Med. 1989 Sep 1;170(3):827-45
2504877
Annu Rev Immunol. 1995;13:251-76
7612223
J Immunol. 2009 Feb 15;182(4):2176-84
19201871
Immunol Rev. 2004 Dec;202:96-105
15546388
N Engl J Med. 2005 Sep 22;353(12):1261-73
16177252
Immunol Rev. 2000 Apr;174:210-25
10807518
J Invest Dermatol. 1998 Dec;111(6):1053-7
9856816
J Exp Med. 1998 Apr 20;187(8):1225-34
9547334
J Autoimmun. 2008 Nov;31(3):252-6
18502610
J Exp Med. 1995 Nov 1;182(5):1301-14
7595201
J Exp Med. 2008 Jul 7;205(7):1535-41
18573909
J Exp Med. 1987 Oct 1;166(4):1084-97
2443596
Clin Exp Immunol. 2009 Mar;155(3):577-86
19094117
J Exp Med. 1995 Jan 1;181(1):399-404
7528775