SOCS3 promotes inflammation and apoptosis via inhibiting JAK2/STAT3 signaling pathway in 3T3-L1 adipocyte

Immunobiology. 2015 Aug;220(8):947-53. doi: 10.1016/j.imbio.2015.02.004. Epub 2015 Feb 14.

Abstract

The suppressor of cytokine signaling 3 (SOCS3) is an established negative feedback regulation transcription factor associated with leptin, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and growth hormone (GH). However, the regulatory mechanism of SOCS3 on inflammation and apoptosis of adipocyte is still not clear. In this study, we found an increased expression of adipocyte inflammatory cytokines TNF-α and IL-6 due to leptin treatment. Meanwhile Caspase3, a key executioner of apoptosis, was also elevated in this process. In addition, we observed that SOCS3 could promote inflammation whereas SOCS3 interference reversed this effect in LPS-induced adipocytes inflammatory model. Moreover, the expression of apoptosis-associated genes Bax, cleaved-Caspase9 and cleaved-Caspase3 were elevated along with decreased Bcl-2 expression as detected with Western blot and ELISA assay. The phosphorylation level of JAK2/STAT3 signal was inhibited by SOCS3 along with the elevated expression of IL-6, TNF-α and Caspase3. We also demonstrated that stable knockdown of SOCS3 along with SD1008, a specific inhibitor of JAK2/STAT3 signaling pathway, could significantly inhibit inflammation and apoptosis of adipocyte. Altogether, these results inferred that SOCS3 promotes adipocyte apoptosis by both aggravating inflammation and inhibiting the activity of JAK2/STAT3 signaling pathway.

Keywords: Adipocyte; Apoptosis; Inflammation; JAK/STAT signaling pathway; SOCS3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / physiology*
  • Animals
  • Apoptosis*
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Gene Expression Regulation
  • Inflammation / drug therapy
  • Inflammation / immunology*
  • Interferon-gamma / metabolism
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Janus Kinase 2 / antagonists & inhibitors
  • Janus Kinase 2 / metabolism*
  • Leptin / immunology
  • Mice
  • Phosphorylation
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / drug effects
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Suppressor of Cytokine Signaling Proteins / metabolism*
  • Tropanes / pharmacology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • 8-benzyl-4-oxo-8-azabicyclo(3.2.1)oct-2-ene-6,7-dicarboxylic acid
  • Interleukin-6
  • Leptin
  • STAT3 Transcription Factor
  • Suppressor of Cytokine Signaling Proteins
  • Tropanes
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Jak2 protein, mouse
  • Janus Kinase 2
  • Caspase 3