Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis.
The pathogenesis of primary biliary cirrhosis (PBC) remains enigmatic. In order to address this issue, we analyzed by laser capture microdissection and real-time reverse transcription-polymerase chain reaction the site-specific expression of messenger RNA (mRNA) for cytokines (interferon (IFN)-alpha, -beta, -gamma, interleukin (IL)-1beta, -4, -6, -10, -12p40, -18, tumor necrosis factor-alpha) and toll-like receptors (TLRs) (TLR-2, -3, -4, -7, -9) in portal tract and liver parenchyma from patients with early-stage PBC. Expression of IFN-alpha, -beta and TLR-3 proteins was also studied by immunohistochemistry. Autoimmune hepatitis (AIH) and chronic hepatitis C (CHC) served as disease controls. The expression levels of type I IFN (IFN-alpha, -beta) and TLR-3 mRNAs, which are known to induce type I IFN, were significantly higher in portal tract and liver parenchyma as compared to AIH and CHC. A strong positive correlation between the mRNA levels of type I IFN and TLR-3 was also seen in both areas. Immunohistologically, IFN-alpha is present in the mononuclear cells in portal tract and sinusoidal cells. Macrophages in portal tract and hepatocytes expressed IFN-beta and TLR-3. Furthermore, the level of IFN-alpha mRNA in the portal tract was positively correlated with serum alkaline phosphatase. In conclusion, these data indicate that TLR-3 and type I IFN signaling pathways are active in both the portal tract and liver parenchyma of early-stage PBC, and form the basis for our hypothesis that these signaling pathways are involved in the pathophysiology of PBC.
Takii
Yasushi
Y
Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Nagasaki 856-8562, Japan.
Nakamura
Minoru
M
Ito
Masahiro
M
Yokoyama
Terufumi
T
Komori
Atsumasa
A
Shimizu-Yoshida
Yuki
Y
Nakao
Rumiko
R
Kusumoto
Koichiro
K
Nagaoka
Shinya
S
Yano
Koji
K
Abiru
Seigo
S
Ueki
Toshihito
T
Matsumoto
Takehiro
T
Daikoku
Manabu
M
Taniguchi
Ken
K
Fujioka
Hikaru
H
Migita
Kiyoshi
K
Yatsuhashi
Hiroshi
H
Nakashima
Masahiro
M
Harada
Mine
M
Ishibashi
Hiromi
H
D000368:Aged; D000469:Alkaline Phosphatase / Q000097:blood; D001659:Biliary Tract / Q000378:metabolism / Q000473:pathology; D001707:Biopsy, Needle; D005260:Female; D019698:Hepatitis C, Chronic / Q000378:metabolism / Q000473:pathology; D019693:Hepatitis, Autoimmune / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D007834:Lasers; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D042282:Microdissection; D008875:Middle Aged; D011168:Portal System / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D015854:Up-Regulation
D007370:Interferon Type I; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495344:TLR3 protein, human; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D000469:Alkaline Phosphatase