Proteasome inhibitors induce heat shock response and increase IL-6 expression in human intestinal epithelial cells

Timothy A. Pritts, Eric S. Hungness, Dan D. Hershko, Bruce Robb, Xiaoyan Sun, Guang Ju Luo, Josef E. Fischer, Hector R. Wong, Per Olof Hasselgren

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

In previous studies, the heat shock response, induced by hyperthermia or sodium arsenite, increased interleukin (IL)-6 production in intestinal mucosa and cultured human enterocytes. A novel way to induce the heat shock response, documented in other cell types, is treatment with proteasome inhibitors. It is not known if proteasome inhibition induces heat shock in enterocytes or influences IL-6 production. Here we tested the hypothesis that treatment of cultured Caco-2 cells, a human intestinal epithelial cell line, with proteasome inhibitors induces the heat shock response and stimulates IL-6 production. Treatment of Caco-2 cells with one of the proteasome inhibitors MG-132 or lactacystin activated the transcription factor heat shock factors (HSF)-1 and -2 and upregulated cellular levels of the 72-kDa heat shock protein HSP-72. The same treatment resulted in increased gene and protein expression of IL-6, a response that was blocked by quercetin. Additional experiments revealed that the IL-6 gene promoter contains a HSF-responsive element and that the IL-6 gene may be regulated by the heat shock response. The present results suggest that proteasome inhibition induces heat shock response and IL-6 production in enterocytes and that IL-6 may be a heat shock-responsive gene, at least under certain circumstances. The observations are important considering the multiple biological roles of IL-6, both locally in the gut mucosa and systemically, and considering recent proposals in the literature to use proteasome inhibitors in the clinical setting to induce the heat shock response.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume282
Issue number4 51-4
StatePublished - 2002
Externally publishedYes

Fingerprint

Heat-Shock Response
Proteasome Inhibitors
Interleukin-6
Epithelial Cells
Enterocytes
Shock
Caco-2 Cells
Hot Temperature
Proteasome Endopeptidase Complex
HSP72 Heat-Shock Proteins
Genes
Induced Hyperthermia
Quercetin
Therapeutics
Intestinal Mucosa
Cultured Cells
Mucous Membrane
Gene Expression
Cell Line

Keywords

  • Cytokine
  • Enterocyte
  • Intestine
  • Mucosa
  • Stress response

ASJC Scopus subject areas

  • Physiology

Cite this

Proteasome inhibitors induce heat shock response and increase IL-6 expression in human intestinal epithelial cells. / Pritts, Timothy A.; Hungness, Eric S.; Hershko, Dan D.; Robb, Bruce; Sun, Xiaoyan; Luo, Guang Ju; Fischer, Josef E.; Wong, Hector R.; Hasselgren, Per Olof.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 282, No. 4 51-4, 2002.

Research output: Contribution to journalArticle

Pritts, Timothy A. ; Hungness, Eric S. ; Hershko, Dan D. ; Robb, Bruce ; Sun, Xiaoyan ; Luo, Guang Ju ; Fischer, Josef E. ; Wong, Hector R. ; Hasselgren, Per Olof. / Proteasome inhibitors induce heat shock response and increase IL-6 expression in human intestinal epithelial cells. In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2002 ; Vol. 282, No. 4 51-4.
@article{4f97256905fd463f9fd3a82680763ec2,
title = "Proteasome inhibitors induce heat shock response and increase IL-6 expression in human intestinal epithelial cells",
abstract = "In previous studies, the heat shock response, induced by hyperthermia or sodium arsenite, increased interleukin (IL)-6 production in intestinal mucosa and cultured human enterocytes. A novel way to induce the heat shock response, documented in other cell types, is treatment with proteasome inhibitors. It is not known if proteasome inhibition induces heat shock in enterocytes or influences IL-6 production. Here we tested the hypothesis that treatment of cultured Caco-2 cells, a human intestinal epithelial cell line, with proteasome inhibitors induces the heat shock response and stimulates IL-6 production. Treatment of Caco-2 cells with one of the proteasome inhibitors MG-132 or lactacystin activated the transcription factor heat shock factors (HSF)-1 and -2 and upregulated cellular levels of the 72-kDa heat shock protein HSP-72. The same treatment resulted in increased gene and protein expression of IL-6, a response that was blocked by quercetin. Additional experiments revealed that the IL-6 gene promoter contains a HSF-responsive element and that the IL-6 gene may be regulated by the heat shock response. The present results suggest that proteasome inhibition induces heat shock response and IL-6 production in enterocytes and that IL-6 may be a heat shock-responsive gene, at least under certain circumstances. The observations are important considering the multiple biological roles of IL-6, both locally in the gut mucosa and systemically, and considering recent proposals in the literature to use proteasome inhibitors in the clinical setting to induce the heat shock response.",
keywords = "Cytokine, Enterocyte, Intestine, Mucosa, Stress response",
author = "Pritts, {Timothy A.} and Hungness, {Eric S.} and Hershko, {Dan D.} and Bruce Robb and Xiaoyan Sun and Luo, {Guang Ju} and Fischer, {Josef E.} and Wong, {Hector R.} and Hasselgren, {Per Olof}",
year = "2002",
language = "English (US)",
volume = "282",
journal = "American Journal of Physiology - Renal Physiology",
issn = "1931-857X",
publisher = "American Physiological Society",
number = "4 51-4",

}

TY - JOUR

T1 - Proteasome inhibitors induce heat shock response and increase IL-6 expression in human intestinal epithelial cells

AU - Pritts, Timothy A.

AU - Hungness, Eric S.

AU - Hershko, Dan D.

AU - Robb, Bruce

AU - Sun, Xiaoyan

AU - Luo, Guang Ju

AU - Fischer, Josef E.

AU - Wong, Hector R.

AU - Hasselgren, Per Olof

PY - 2002

Y1 - 2002

N2 - In previous studies, the heat shock response, induced by hyperthermia or sodium arsenite, increased interleukin (IL)-6 production in intestinal mucosa and cultured human enterocytes. A novel way to induce the heat shock response, documented in other cell types, is treatment with proteasome inhibitors. It is not known if proteasome inhibition induces heat shock in enterocytes or influences IL-6 production. Here we tested the hypothesis that treatment of cultured Caco-2 cells, a human intestinal epithelial cell line, with proteasome inhibitors induces the heat shock response and stimulates IL-6 production. Treatment of Caco-2 cells with one of the proteasome inhibitors MG-132 or lactacystin activated the transcription factor heat shock factors (HSF)-1 and -2 and upregulated cellular levels of the 72-kDa heat shock protein HSP-72. The same treatment resulted in increased gene and protein expression of IL-6, a response that was blocked by quercetin. Additional experiments revealed that the IL-6 gene promoter contains a HSF-responsive element and that the IL-6 gene may be regulated by the heat shock response. The present results suggest that proteasome inhibition induces heat shock response and IL-6 production in enterocytes and that IL-6 may be a heat shock-responsive gene, at least under certain circumstances. The observations are important considering the multiple biological roles of IL-6, both locally in the gut mucosa and systemically, and considering recent proposals in the literature to use proteasome inhibitors in the clinical setting to induce the heat shock response.

AB - In previous studies, the heat shock response, induced by hyperthermia or sodium arsenite, increased interleukin (IL)-6 production in intestinal mucosa and cultured human enterocytes. A novel way to induce the heat shock response, documented in other cell types, is treatment with proteasome inhibitors. It is not known if proteasome inhibition induces heat shock in enterocytes or influences IL-6 production. Here we tested the hypothesis that treatment of cultured Caco-2 cells, a human intestinal epithelial cell line, with proteasome inhibitors induces the heat shock response and stimulates IL-6 production. Treatment of Caco-2 cells with one of the proteasome inhibitors MG-132 or lactacystin activated the transcription factor heat shock factors (HSF)-1 and -2 and upregulated cellular levels of the 72-kDa heat shock protein HSP-72. The same treatment resulted in increased gene and protein expression of IL-6, a response that was blocked by quercetin. Additional experiments revealed that the IL-6 gene promoter contains a HSF-responsive element and that the IL-6 gene may be regulated by the heat shock response. The present results suggest that proteasome inhibition induces heat shock response and IL-6 production in enterocytes and that IL-6 may be a heat shock-responsive gene, at least under certain circumstances. The observations are important considering the multiple biological roles of IL-6, both locally in the gut mucosa and systemically, and considering recent proposals in the literature to use proteasome inhibitors in the clinical setting to induce the heat shock response.

KW - Cytokine

KW - Enterocyte

KW - Intestine

KW - Mucosa

KW - Stress response

UR - http://www.scopus.com/inward/record.url?scp=0036081709&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036081709&partnerID=8YFLogxK

M3 - Article

VL - 282

JO - American Journal of Physiology - Renal Physiology

JF - American Journal of Physiology - Renal Physiology

SN - 1931-857X

IS - 4 51-4

ER -