Effect of transforming growth factor-beta1 on human intrahepatic cholangiocarcinoma cell growth.
OBJECTIVE
To elucidate the biological effects of transforming growth factor-beta1 (TGF-beta1) on intrahepatic cholan-giocarcinoma (ICC).


METHODS
We investigated the effects of TGF-beta1 on human ICC cell lines (HuCCT1, MEC, and HuH-28) by monitoring the influence of TGF-beta1 on tumor growth and interleukin-6 (IL-6) expression in ICC cells.


RESULTS
All three human ICC cell lines produced TGF-beta1 and demonstrated accelerated growth in the presence of TGF-beta1 with no apoptotic effect. Studies on HuCCT1 revealed a TGF-beta1-induced stimulation of the expression of TGF-beta1, as well as a decrease in TGF-beta1 mRNA expression induced by neutralizing anti-TGF-beta1 antibody. These results indicate that TGF-beta1 stimulates the production and function of TGF-beta1 in an autocrine fashion. Further, IL-6 secretion was observed in all three cell lines and exhibited an inhibitory response to neutralizing anti-TGF-beta1 antibody. Experiments using HuCCT1 revealed a TGF-beta1-induced acceleration of IL-6 protein expression and mRNA levels. These findings demonstrate a functional interaction between TGF-beta1 and IL-6. All three cell lines proliferated in the presence of IL-6. In contrast, TGF-beta1 induced no growth effect in HuCCT1 in the presence of small interfering RNA against a specific cell surface receptor of IL-6 and signal transducer and activator of transcription-3.


CONCLUSIONS
ICC cells produce TGF-beta1 and confer a TGF-beta1-induced growth effect in an autocrine fashion. TGF-beta1 activates IL-6 production, and the functional interaction between TGF-beta1 and IL-6 contributes to ICC cell growth by TGF-beta1.
Shimizu
Tetsuya
T
Surgery for Organ Function and Biological Regulation, Graduate school of medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. tetsuya@nms.ac.jp
Yokomuro
Shigeki
S
Mizuguchi
Yoshiaki
Y
Kawahigashi
Yutaka
Y
Arima
Yasuo
Y
Taniai
Nobuhiko
N
Mamada
Yasuhiro
Y
Yoshida
Hiroshi
H
Akimaru
Koho
K
Tajiri
Takashi
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008907:Mink; D017346:Protein Serine-Threonine Kinases; D034622:RNA Interference / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000502:physiology*
D015850:Interleukin-6; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D018125:Receptors, Transforming Growth Factor beta; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053773:Transforming Growth Factor beta1; C113250:interleukin-6 receptor alpha; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II