Proinflammatory cytokines inhibit secretion in rat bile duct epithelium

被引:109
作者
Spirlì, C
Nathanson, MH
Fiorotto, R
Duner, E
Denson, LA
Sanz, JM
Di Virgilio, F
Okolicsanyi, L
Casagrande, F
Strazzabosco, M
机构
[1] Osped Riuniti Bergamo, Div Gastroenterol, I-24128 Bergamo, Italy
[2] Univ Padua, Med Clin 1, Dept Med & Surg Sci, Padua, Italy
[3] Univ Padua, Dept Surg & Gastroenterol Sci, Padua, Italy
[4] Yale Univ, Dept Med, New Haven, CT 06520 USA
[5] Yale Univ, Dept Pediat, New Haven, CT 06520 USA
[6] Univ Ferrara, Dept Expt & Diagnost Med, I-44100 Ferrara, Italy
关键词
D O I
10.1053/gast.2001.25516
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background & Aims: Cholestatic disorders often are associated with portal inflammation, but whether or how inflammation contributes to cholestasis is unknown. Thus we studied the effects of proinflammatory cytokines on bile duct epithelia secretory mechanisms. Methods: Isolated bile duct units (IBDUs) were cultured with interleukin (IL)-6, interferon gamma, tumor necrosis factor (TNF)-alpha, and IL-1 alone or in combination. Ductular secretion was measured using video-optical planimetry. Bicarbonate and Cl- transport were assessed microfluorimetric measuring pH, (BCECF) and [Cl-](i) transients (MEQ). Expression of Cl-/HCO3- exchanger (AE-2), cystic fibrosis transmembrane conductance regulator (CFTR), and the secretin receptor (SR) were assessed by ribonuclease protection assay. Cellular cyclic adenosine monophosphate (cAMP) levels were studied by enzymatic immunoassay. Paracellular permeability was assessed using fluorescein-labeled dextrans (FD) in cholangiocyte monolayers (NRC-1). Results: Although not effective when given alone, each combination of IL-6, interferon gamma, IL-1, and TNF-alpha inhibited secretion in IBDU. Cytokines inhibited cAMP formation, AE-2 activity, and cyclic AMP-dependent Cl- efflux, but not that induced by purinergic agonists. AE-2 gene expression was unaffected by proinflammatory cytokines, whereas CFTR and SR expression was increased. In addition, paracellular transit of FD across NRC-1 monolayers was increased. Conclusions: Inflammatory cytokines inhibit cAMP-dependent fluid secretion in cholangiocytes and impair the barrier functions of biliary epithelia. These changes may represent the molecular mechanisms by which inflammation leads to ductular cholestasis in vivo.
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页码:156 / 169
页数:14
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