Leptin enhances TNF-alpha production via p38 and JNK MAPK in LPS-stimulated Kupffer cells.
Leptin is now recognized as a proinflammatory cytokine and thought to be a progressive factor for non-alcoholic steatohepatitis (NASH). Here we showed the effects of leptin on the production of TNF-alpha (tumor necrosis factor-alpha) by Kupffer cells (KCs) with signal transduction. Leptin enhanced TNF-alpha production accompanied by a dose-dependent increase of MAPK activity in lipopolysaccharide (LPS)-stimulated KCs. SB203580 and JNK inhibitor I, specific inhibitors of P38 and JNK, inhibited TNF-alpha production in KCs but PD98059, an inhibitor of the ERK pathway, did not affect TNF-alpha production by KCs. Recombinant constitutively active adenovirus (Ad)-MKK6 and-MKK7 increased TNF-alpha production in KCs with activation of P38 and JNK without any change by Ad-MEK1 delivery. On the other hand, KCs isolated from the Zucker rat (fa/fa), a leptin receptor-deficient rat, showed reduced production of TNF-alpha on stimulation with LPS. The delivery of Ad-MKK6 and-MKK7, but not Ad-MEK1, increased TNF-alpha production in KCs of Zucker rats with activation of P38 and JNK. Addition of leptin to normal rats increased LPS-induced hepatic TNF-alpha production in vivo and leptin receptor-deficient Zucker rats showed reduced hepatic TNF-alpha production on addition of LPS in vivo. These findings indicate that P38 and JNK pathways are involved in the signal transduction of leptin enhancement of LPS-induced TNF-alpha production.
Department of Gastroenterology and Hepatology, School of Medicine, Yamaguchi University, Minami Kogushi 1-1-1, Ube, Yamaguchi-Pref. 755-8505, Japan.
Jinhua
J
Shen
Isao
I
Sakaida
Koichi
K
Uchida
Shuji
S
Terai
Kiwamu
K
Okita
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D020738:Leptin; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases