Tumor necrosis factor-alpha induces c-jun during the regenerative response to liver injury.
After liver injury, remaining hepatocytes proliferate to regenerate the liver. Although the precise mechanisms that initiate and localize regeneration are unknown, local induction of c-jun is a critical, early step in the response. Treatment of rats with antibodies to tumor necrosis factor-alpha (TNF-alpha), a mediator of liver injury, inhibits regenerative induction of jun nuclear kinase activity and nuclear c-jun expression and alters the DNA binding activity of the c-jun transcription factor, AP-1, in liver. Pretreatment with anti-TNF antibodies does not affect pulmonary or renal c-jun expression or AP-1 binding activity post-partial hepatectomy. In primary hepatocyte cultures, TNF-alpha directly promotes the proliferative actions of mitogens, supporting in vivo evidence that it sensitizes hepatocytes to mitogens. Thus local release of TNF may act in a paracrine fashion to initiate regeneration in the injured liver by promoting induction of critical growth-related genes, such as c-jun.
Diehl
A M
AM
Johns Hopkins University, Baltimore, Maryland 21205.
Yin
M
M
Fleckenstein
J
J
Yang
S Q
SQ
Lin
H Z
HZ
Brenner
D A
DA
Westwick
J
J
Bagby
G
G
Nelson
S
S
D000818:Animals; D000906:Antibodies / Q000276:immunology; D001483:Base Sequence; D004247:DNA / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects*; D016758:Genes, jun; D006498:Hepatectomy / Q000379:methods; D008099:Liver / Q000293:injuries*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology*
D000906:Antibodies; D015345:Oligonucleotide Probes; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D004247:DNA