title: Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis.
abstract: 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.
authors.affiliation: Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Nagasaki 856-8562, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Takii
authors.forename: Minoru
authors.initials: M
authors.lastname: Nakamura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ito
authors.forename: Terufumi
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Atsumasa
authors.initials: A
authors.lastname: Komori
authors.forename: Yuki
authors.initials: Y
authors.lastname: Shimizu-Yoshida
authors.forename: Rumiko
authors.initials: R
authors.lastname: Nakao
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kusumoto
authors.forename: Shinya
authors.initials: S
authors.lastname: Nagaoka
authors.forename: Koji
authors.initials: K
authors.lastname: Yano
authors.forename: Seigo
authors.initials: S
authors.lastname: Abiru
authors.forename: Toshihito
authors.initials: T
authors.lastname: Ueki
authors.forename: Takehiro
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Manabu
authors.initials: M
authors.lastname: Daikoku
authors.forename: Ken
authors.initials: K
authors.lastname: Taniguchi
authors.forename: Hikaru
authors.initials: H
authors.lastname: Fujioka
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Migita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yatsuhashi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakashima
authors.forename: Mine
authors.initials: M
authors.lastname: Harada
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ishibashi
mesh_terms: 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
chemical_list: 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