Shen Jinhua, Sakaida Isao, Uchida Koichi, Terai Shuji, Okita Kiwamu
Department of Gastroenterology and Hepatology, School of Medicine, Yamaguchi University, Minami Kogushi 1-1-1, Ube, Yamaguchi-Pref. 755-8505, Japan.
Life Sci. 2005 Aug 12;77(13):1502-15. doi: 10.1016/j.lfs.2005.04.004.
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.
瘦素现在被认为是一种促炎细胞因子，并且被认为是非酒精性脂肪性肝炎（NASH）的一个进展因素。在此我们展示了瘦素通过信号转导对库普弗细胞（KCs）产生肿瘤坏死因子-α（TNF-α）的影响。瘦素增强了TNF-α的产生，同时在脂多糖（LPS）刺激的KCs中丝裂原活化蛋白激酶（MAPK）活性呈剂量依赖性增加。SB203580和JNK抑制剂I，即P38和JNK的特异性抑制剂，抑制了KCs中TNF-α的产生，但ERK途径的抑制剂PD98059对KCs产生TNF-α没有影响。重组组成型活性腺病毒（Ad）-MKK6和-MKK7通过激活P38和JNK增加了KCs中TNF-α的产生，而Ad-MEK1的递送没有产生任何变化。另一方面，从瘦素受体缺陷大鼠Zucker大鼠（fa/fa）分离出的KCs在LPS刺激下TNF-α的产生减少。Ad-MKK6和-MKK7的递送，但不是Ad-MEK1，通过激活P38和JNK增加了Zucker大鼠KCs中TNF-α的产生。向正常大鼠体内添加瘦素增加了LPS诱导的肝脏TNF-α的产生，而在体内添加LPS时，瘦素受体缺陷的Zucker大鼠肝脏TNF-α的产生减少。这些发现表明P38和JNK途径参与了瘦素增强LPS诱导的TNF-α产生的信号转导。
