Inhibition of p38 mitogen-activated protein kinase attenuates experimental autoimmune hepatitis: involvement of nuclear factor kappa B.
OBJECTIVE
To investigate the role of p38 mitogen-activated protein kinase (p38MAPK) in murine experimental autoimmune hepatitis (EAH).


METHODS
To induce EAH, the syngeneic S-100 antigen emulsified in complete Freud's adjuvant was injected intraperitoneally into adult male C57Bl/6 mice. Liver injury was assessed by serum ALT and liver histology. The expression and activity of p38 MAPK were measured by Western blot and kinase activity assays. In addition, DNA binding activities of nuclear factor kappa B (NF-kappaB) were analyzed by electrophoretic mobility shift assay. The effects of SB203580, a specific p38 MAPK inhibitor, on liver injuries and expression of proinflammatory cytokines (interferon-gamma, IL-12, IL-1beta and TNF-alpha) were observed.


RESULTS
The activity of p38 MAPK and NF-kappaB was increased and reached its peak 14 or 21 d after the first syngeneic S-100 administration. Inhibition of p38 MAPK activation by SB203580 decreased the activation of NF-kappaB and the expression of proinflammatory cytokines. Moreover, hepatic injuries were improved significantly after SB203580 administration.


CONCLUSIONS
p38 MAPK and NF-kappaB play an important role in an animal model of autoimmune hepatitis (AIH) induced by autoantigens.
Ma
Xiong
X
Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200001, China.
Jia
Yi-Tao
YT
Qiu
De-Kai
DK
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001324:Autoantigens / Q000276:immunology / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019693:Hepatitis, Autoimmune / Q000276:immunology / Q000503:physiopathology* / Q000517:prevention & control*; D007093:Imidazoles / Q000494:pharmacology; D008099:Liver / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D009418:S100 Proteins / Q000276:immunology / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology*
D001324:Autoantigens; D016207:Cytokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016328:NF-kappa B; D011725:Pyridines; D009418:S100 Proteins; D000410:Alanine Transaminase; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
Arthritis Rheum. 2000 Nov;43(11):2501-12
11083274
Toxicol Sci. 2000 Oct;57(2):345-52
11006364
Ann Rheum Dis. 1999 Jun;58(6):382-5
10340964
Int Immunopharmacol. 2004 Jan;4(1):25-36
14975357
J Am Soc Nephrol. 2003 Jan;14(1):57-67
12506138
Zhonghua Gan Zang Bing Za Zhi. 2004 Jan;12(1):44-6
14761285
Cell Signal. 2000 Jan;12(1):1-13
10676842
Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15671-6
9861028
J Hepatol. 1994 Nov;21(5):816-21
7534321
Hepatology. 2003 Oct;38(4):820-8
14512869
Oncogene. 1999 Nov 22;18(49):6853-66
10602461
Hum Immunol. 2004 Jul;65(7):683-91
15301856
Hepatology. 1999 Oct;30(4):851-6
10498633
Semin Liver Dis. 2002 Nov;22(4):325-38
12447705
Cell. 1996 Oct 4;87(1):13-20
8858144
Clin Exp Immunol. 1990 Dec;82(3):473-8
2265486
Hepatology. 1990 Jan;11(1):24-30
2271015
Zhonghua Gan Zang Bing Za Zhi. 2001 Aug;9(4):226-8
11602055
Mol Biol Cell. 2004 Apr;15(4):2013-26
14767066
Mayo Clin Proc. 2001 Dec;76(12):1237-52
11761505
Mol Pharmacol. 1995 Sep;48(3):433-42
7565623
J Biol Chem. 1997 Sep 19;272(38):23668-74
9295308
Nature. 1994 Dec 22-29;372(6508):739-46
7997261
Annu Rev Immunol. 2002;20:55-72
11861597
J Hepatol. 1992 Jan;14(1):48-53
1737915
Hepatology. 1998 Jun;27(6):1536-43
9620324
FASEB J. 2004 Oct;18(13):1550-2
15289440
Curr Opin Pharmacol. 2004 Aug;4(4):372-7
15251131
Clin Liver Dis. 2002 Aug;6(3):727-37
12362577
Semin Liver Dis. 2002 Nov;22(4):339-52
12447706
J Pharmacol Exp Ther. 1997 Sep;282(3):1615-22
9316879
Am J Physiol Gastrointest Liver Physiol. 2003 Mar;284(3):G525-35
12466145
Virus Res. 2003 Apr;92(2):131-40
12686421
Shock. 2002 Aug;18(2):99-106
12166787
Life Sci. 2004 Mar 26;74(19):2339-64
15027449
Gastroenterology. 1999 Sep;117(3):645-52
10464141