The role of innate immunity in the pathogenesis of experimental autoimmune pancreatitis in mice.
OBJECTIVE
To determine the role of innate immunity in the development of autoimmune pancreatitis in mice induced by toll-like receptor (TLR) stimulation.


METHODS
Six-week-old female MRL/Mp mice were injected intraperitoneally with polyinosinic polycytidylic acid (poly I:C) or lipopolysaccharide (LPS) at doses of 5 mg/kg body weight twice weekly for 12 weeks. The mice were killed, and the severity of pancreatitis was graded using a histological scoring system. Serum cytokine levels of mice with pancreatitis and mice that were given a single injection of TLR ligands were measured using enzyme-linked immunosorbent assays. The effect of TLR stimulation on the development of pancreatitis was also examined using C57BL/6 interleukin (IL)-10-deficient mice.


RESULTS
Administration of poly I:C accelerated the development of pancreatitis in MRL/Mp mice, but LPS did not. Serum levels of IL-10 and IL-12 were significantly elevated in mice with autoimmune pancreatitis. A single injection of LPS markedly increased serum levels of interferon-γ, tumor necrosis factor-α, IL-10, and IL-12 compared with those of poly I:C-treated mice. Treatment with not only poly I:C but also LPS induced pancreatitis in IL-10-deficient mice but not in wild-type mice.


CONCLUSIONS
Repeated stimulation of innate immunity induces autoimmunity in the pancreas of mice via an imbalance between proinflammatory and anti-inflammatory cytokines.
Nishio
Akiyoshi
A
Third Department of Internal Medicine, Kansai Medical University, Moriguchi, Japan. nishioa@takii.kmu.ac.jp
Asada
Masanori
M
Uchida
Kazushige
K
Fukui
Toshiro
T
Chiba
Tsutomu
T
Okazaki
Kazuichi
K
D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology* / Q000276:immunology; D005260:Female; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000502:physiology; D018664:Interleukin-12 / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D010195:Pancreatitis / Q000209:etiology* / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics
D051193:Toll-Like Receptors; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma