Leptin induces IL-6 expression through OBRl receptor signaling pathway in human synovial fibroblasts

PLoS One. 2013 Sep 27;8(9):e75551. doi: 10.1371/journal.pone.0075551. eCollection 2013.

Abstract

Background: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Fibroblasts / metabolism*
  • Humans
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism
  • Interleukin-6 / genetics*
  • Interleukin-6 / metabolism*
  • Leptin / genetics
  • Leptin / metabolism*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering / genetics
  • Receptors, Leptin / genetics
  • Receptors, Leptin / metabolism*
  • Signal Transduction / genetics*
  • Synovial Membrane / metabolism*
  • Transfection

Substances

  • IL6 protein, human
  • Insulin Receptor Substrate Proteins
  • Interleukin-6
  • Leptin
  • RNA, Small Interfering
  • Receptors, Leptin
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt

Grants and funding

This study was supported by grants from the National Science Council of Taiwan (NSC99-2320-B-039-003-MY3; 100-2320-B-039-028-MY3) and Department of Health Executive Yuan (DOH10220). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.