Cholangiocytes as immune modulators in rotavirus-induced murine biliary atresia.
OBJECTIVE
Biliary atresia (BA) is a progressive disease characterized by bile duct inflammation and fibrosis. The aetiology is unknown and may be due to a virus-induced, autoimmune-mediated injury of cholangiocytes. Cholangiocytes are not only targets of injury but may also modulate hepatic inflammation. The aim of this study was to determine the immune profile of murine cholangiocytes and the ability to function as antigen-presenting cells (APCs) in culture with Rhesus rotavirus (RRV), poly I:C (viral mimic) or interferon-gamma/tumour necrosis factor-alpha.


RESULTS
Both the cholangiocyte cell line (long-term culture) and fresh, ex vivo cholangiocytes expressed APC surface markers major histocompatibility complex (MHC)-class I and II and CD40, while only the cultured cell line expressed costimulatory molecules B7-1 and B7-2. Despite APC expression, cultured cholangiocytes were unable to function as competent APCs in T-cell proliferation assays. Furthermore, both cultured and ex vivo cholangiocytes expressed RNA transcripts for many pro-inflammatory cytokines and chemokines.


CONCLUSIONS
Although cholangiocytes contain APC molecules, they are incompetent at antigen presentation and cannot elicit effective T-cell activation. Upregulation of MHC-class I and II found in BA mice may serve to prime the cholangiocyte as a target for immune-mediated injury. Cholangiocytes produced many pro-inflammatory cytokines and chemokines in the setting of RRV infection and T-helper type 1 cytokine milieu, suggesting a role of cholangiocytes as immune modulators promoting the ongoing inflammation that exists in RRV-induced BA.
Barnes
Barrett H
BH
Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology & Nutrition, The Children's Hospital, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
Tucker
Rebecca M
RM
Wehrmann
Fabian
F
Mack
Doug G
DG
Ueno
Yoshiyuki
Y
Mack
Cara L
CL
D000818:Animals; D000831:Animals, Newborn; D000938:Antigen-Presenting Cells / Q000276:immunology; D017734:Bile Ducts, Extrahepatic / Q000276:immunology* / Q000473:pathology; D001656:Biliary Atresia / Q000276:immunology / Q000821:virology*; D002460:Cell Line; D002469:Cell Separation; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006649:Histocompatibility Antigens / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D012401:Rotavirus / Q000502:physiology*; D012400:Rotavirus Infections / Q000276:immunology / Q000821:virology*; D013601:T-Lymphocytes / Q000276:immunology; D014779:Virus Replication
D018925:Chemokines; D006649:Histocompatibility Antigens