Department of Orthopedic Surgery, Taichung Hospital, Department of Health Executive Yuan, Taichung, Taiwan ; Department of Nursing, National Taichung University of Science and Technology, Taichung, Taiwan ; School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan ; Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan.
PLoS One. 2013 Sep 27;8(9):e75551. doi: 10.1371/journal.pone.0075551. eCollection 2013.
Leptin, an adipocyte-secreted hormone that centrally regulates weight control, may exert proinflammatory effects in the joint, depending on the immune response. Leptin is abundantly expressed in osteoarthritis (OA) cartilage and synovium. However, the relationship between leptin and interleukin-6 (IL-6) in OA synovial fibroblasts (OASFs) remains obscure.
METHODOLOGY/PRINCIPAL FINDINGS: Stimulation of OASFs with leptin induced IL-6 expression in a concentration- and time-dependent manner. OASFs expressed the long (OBRl) and short (OBRs) isoforms of the leptin receptor. However, OBRl, but not OBRs, antisense oligonucleotide (AS-ODN) abolished the leptin-mediated increase of IL-6 expression. Transfection with insulin receptor substrate (IRS)-1 siRNA decreased leptin-induced IL-6 production. In addition, pretreatment of cells with PI3K, Akt, or AP-1 inhibitor also inhibited the potentiating action of leptin. Leptin-induced AP-1 activation was inhibited by OBRl, IRS-1, PI3K, or Akt inhibitors and siRNAs.
CONCLUSIONS/SIGNIFICANCE: Our results showed that leptin activates the OBRl receptor, which in turn activates IRS-1, PI3K, Akt, and AP-1 pathway, leading to up-regulation of IL-6 expression.
瘦素是一种脂肪细胞分泌的激素，它可以通过中枢神经系统调节体重，在关节中可能发挥促炎作用，具体取决于免疫反应。瘦素在骨关节炎（OA）软骨和滑膜中大量表达。然而，瘦素与 OA 滑膜成纤维细胞（OASFs）中的白细胞介素-6（IL-6）之间的关系仍不清楚。
方法/主要发现：瘦素刺激 OASFs 以浓度和时间依赖的方式诱导 IL-6 表达。OASFs 表达瘦素受体的长（OBR1）和短（OBRs）两种同工型。然而，只有 OBR1 反义寡核苷酸（AS-ODN）而非 OBRs 反义寡核苷酸可以消除瘦素介导的 IL-6 表达增加。胰岛素受体底物（IRS）-1 siRNA 的转染降低了瘦素诱导的 IL-6 产生。此外，用 PI3K、Akt 或 AP-1 抑制剂预处理细胞也抑制了瘦素的增强作用。瘦素诱导的 AP-1 激活被 OBR1、IRS-1、PI3K 或 Akt 抑制剂和 siRNAs 抑制。
结论/意义：我们的结果表明，瘦素激活 OBR1 受体，进而激活 IRS-1、PI3K、Akt 和 AP-1 通路，导致 IL-6 表达上调。
