BACKGROUND & AIMS:
Primary sclerosing cholangitis (PSC) is an
autoimmune liver disease with destruction of
hepatic bile ducts. A
high frequency of
biliary epithelial cell antibodies (BEC-Ab) is present in PSC. Here, we studied the mechanisms and
signaling pathways used by these Ab in causing BEC dysfunction. METHODS:
Immunoassays were performed using freshly isolated BECs to study the signaling capacity of purified
immunoglobulin (Ig) G and F(ab)'(2) fractions from 33 patients with PSC with anti-BEC-Ab. RESULTS: We provide evidence that stimulation of BECs with PSC
IgG, but not control
IgG, induced expression of
Toll-like receptor (
TLR) 4 and
TLR9 and specific
phosphorylation of
extracellular signal-regulated kinase (ERK) 1/2 as well as the
transcription factors ELK-1 and nuclear factor kappaB. A specific inhibitor of
ERK1/2 abrogated
phosphorylation of ELK-1 and
protein expression of
TLR4 but not
TLR9 on BECs. TLR-expressing BECs, when further stimulated with
lipopolysaccharide and
CpG DNA, produced high levels of interleukin-1beta, interleukin-8,
interferon gamma,
tumor necrosis factor alpha,
granulocyte-macrophage colony-stimulating factor, and
transforming growth factor beta.
Bile ducts stained positively for
TLR4 and
TLR9 in 58% of
liver specimens taken from patients with PSC with BEC-Ab, as compared with 14% in those without BEC-Ab and also less frequently in diseased control
livers. CONCLUSIONS: Our data show that binding of PSC BEC-Ab initiates
ERK1/2 signaling and up-regulation of
TLR, which upon ligation induces BECs to produce
cytokines/
chemokines, leading to the possible recruitment of
inflammatory cells. Thus, in PSC, BECs are not only targets of the
immune attack but may also be active participants and mediators of their own destruction. BEC-Ab may be critical regulators of
cholangitis in PSC.
