Lipopolysaccharide induces cholangiocyte proliferation via an interleukin-6-mediated activation of p44/p42 mitogen-activated protein kinase.
The biliary epithelium is exposed to mediators of inflammation such as bacterial endotoxin or lipopolysaccharide (LPS) in a variety of inflammatory conditions. These conditions are also characterized by cholangiocyte proliferation and a predisposition to malignancy. Furthermore, LPS can enhance the expression of interleukin-6 (IL-6), a known biliary mitogen. However, the effects of LPS on cholangiocyte proliferation or IL-6 secretion are unknown. Thus, our aims were to determine if LPS stimulates cholangiocyte proliferation by IL-6-dependent signaling pathways. H69 cells derived from normal human intrahepatic cholangiocytes proliferated in response to LPS. Cholangiocytes responded to LPS (and other inflammatory cytokines such as tumor necrosis factor alpha [TNF-alpha] and IL-1beta) by increased secretion of IL-6, which had a mitogenic effect on H69 cells. Preincubation with anti-IL-6 neutralizing antibodies inhibited LPS-induced proliferation. Furthermore, cholangiocytes possessed the IL-6 receptor complex subunits and intact signaling mechanisms leading to activation of signal transducers and activators of transcription (STAT) factors. Although both p38 and p44/p42 mitogen-activated protein kinases (MAPKs) were constitutively present and active in cholangiocytes, IL-6 increased p44/p42, but not p38 MAPK activity. PD098059 inhibited activation of p44/p42 MAPK in cholangiocytes and completely blocked DNA synthesis in response to IL-6 or LPS. These studies identify a critical role for the p44/p42 MAPK in cholangiocyte proliferation and demonstrate that the proliferative response of cholangiocytes to inflammatory mediators such as LPS involves IL-6-mediated activation of the p44/p42 MAPK pathway.
Park
J
J
Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN, USA.
Gores
G J
GJ
Patel
T
T
D001652:Bile Ducts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D015846:Monokines / Q000494:pharmacology; D019947:Receptors, Interleukin-6 / Q000378:metabolism
D004791:Enzyme Inhibitors; D005419:Flavonoids; D015850:Interleukin-6; D008070:Lipopolysaccharides; D015846:Monokines; D019947:Receptors, Interleukin-6; D004247:DNA; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one