1. ¹Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Nagasaki, Japan
2. ²Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
3. ³Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
4. ⁴Tissue and Histopathology Section, Division of Scientific Data Registry, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

Correspondence: Dr M Nakamura, MD, PhD, Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center and Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Kubara 2-1001-1, Omura, Nagasaki 856-8562, Japan. E-mail: nakamuram@nmc.hosp.go.jp

Received 5 January 2005; Revised 15 March 2005; Accepted 15 March 2005; Published online 25 April 2005.

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)-, -, -, interleukin (IL)-1, -4, -6, -10, -12p40, -18, tumor necrosis factor-) 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-, - 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-, -) 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- is present in the mononuclear cells in portal tract and sinusoidal cells. Macrophages in portal tract and hepatocytes expressed IFN- and TLR-3. Furthermore, the level of IFN- 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.