Involvement of Heat-Shock Protein 90 in the interleukin-6-mediated Signaling Pathway Through STAT3

Biochem Biophys Res Commun. 2003 Jan 24;300(4):847-52. doi: 10.1016/s0006-291x(02)02941-8.

Abstract

Interleukin-6 (IL-6) is a multifunctional cytokine playing roles in the immune system, hematopoiesis, and acute phase reactions. IL-6 also regulates the growth of various types of human malignant tumors. Here we demonstrate that IL-6-induced gene expression was suppressed by a specific heat-shock protein 90 (Hsp90) inhibitor, geldanamycin (GA) in human hepatoma Hep3B cells. GA also suppressed the IL-6-induced activation of signal transducer and activator of transcription 3 (STAT3) in a human embryonic kidney carcinoma 293T cells. This inhibitory effect of GA on STAT3 activation was reversed by overexpression of Hsp90. Furthermore, Hsp90 directly bound to STAT3 via its N-terminal region, which interacted with GA. We provide evidence that the action of GA on IL-6 functions was due to the inhibition of direct physical interactions between STAT3 and Hsp90, which represents a novel role of Hsp90 in the IL-6 signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzoquinones
  • Cysteine Proteinase Inhibitors / metabolism
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation
  • Genes, Reporter
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • HSP90 Heat-Shock Proteins / metabolism*
  • Humans
  • Interleukin-6 / metabolism*
  • Lactams, Macrocyclic
  • Quinones / metabolism
  • Recombinant Proteins / metabolism
  • STAT3 Transcription Factor
  • Signal Transduction / physiology*
  • Trans-Activators / metabolism*
  • Tumor Cells, Cultured

Substances

  • Benzoquinones
  • Cysteine Proteinase Inhibitors
  • DNA-Binding Proteins
  • HSP90 Heat-Shock Proteins
  • Interleukin-6
  • Lactams, Macrocyclic
  • Quinones
  • Recombinant Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Trans-Activators
  • geldanamycin