Involvement of heat-shock protein 90 in the interleukin-6-mediated signaling pathway through STAT3.
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.
Sato
Noriko
N
Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-Ku Kita 12 Nishi 6, Sapporo 060-0812, Japan.
Yamamoto
Tetsuya
T
Sekine
Yuichi
Y
Yumioka
Taro
T
Junicho
Akira
A
Fuse
Hideki
H
Matsuda
Tadashi
T
D016227:Benzoquinones; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D047029:Lactams, Macrocyclic; D011809:Quinones / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D016227:Benzoquinones; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D015850:Interleukin-6; D047029:Lactams, Macrocyclic; D011809:Quinones; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; C001277:geldanamycin