Triiodothyronine and interleukin-6 (IL-6) induce expression of HGF in an immortalized rat hepatic stellate cell line.
OBJECTIVE
Despite its being considered a primary mitogen for hepatocytes, triiodothyronine (T3) has no effect on the proliferation of hepatocytes in vitro, and in our studies, induces significant in vivo hepatocyte proliferation only during liver injury. We hypothesized that T3 may affect hepatocytes proliferation indirectly, by inducing other cells in the liver to secrete hepatic mitogens.


METHODS
In vivo studies: Lipopolysaccharide, T3 and a combination of the two were injected into rats, and hepatocyte proliferation was determined by PCNA staining and mitotic index.


METHODS
a rat hepatic stellate cell line (HSC-6T) was cultured with T3, IL-6 and a combination of the two, and we assessed the effect of these cytokine/hormone combinations on the cell proliferation and on secretion of IL-6 and HGF, measured by ELISA. Expression of thyroid hormone receptors was assessed by RT-PCR.


RESULTS
In vivo: T3, together with lipopolysaccharide, enhances PCNA staining and the mitotic index of hepatocytes in the treated rats. In vitro: the hepatic stellate cell line expresses thyroid hormone receptor alpha 1, but not beta 1. Proliferation of stellate cells is not affected by T3, with or without IL-6. T3 has no effect on secreted levels of IL-6 in the stellate cell line. Hepatic stellate cells cultured with T3 and IL-6 show significantly increased amounts of secreted HGF after 48 h in culture.


CONCLUSIONS
T3 may induce hepatocyte proliferation in vivo during injury by turning on expression of HGF in stellate cells and acting together with IL-6.
Kariv
R
R
Liver Unit, Gastroenterology Institute, Tel Aviv Sourasky Medical Center, Weizmann 6, Tel Aviv, Israel.
Enden
A
A
Zvibel
Isab
I
Rosner
G
G
Brill
S
S
Shafritz
D A
DA
Halpern
Z
Z
Oren
R
R
D000818:Animals; D002455:Cell Division / Q000235:genetics*; D002460:Cell Line; D006133:Growth Substances / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis*; D022781:Hepatocytes / Q000187:drug effects*; D015850:Interleukin-6 / Q000378:metabolism*; D008099:Liver / Q000166:cytology; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D008934:Mitogens / Q000096:biosynthesis; D008940:Mitotic Index; D018809:Proliferating Cell Nuclear Antigen; D051381:Rats; D011916:Rats, Inbred F344; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism*
D006133:Growth Substances; D015850:Interleukin-6; D008934:Mitogens; D018809:Proliferating Cell Nuclear Antigen; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D014284:Triiodothyronine; D017228:Hepatocyte Growth Factor