Coupling of inflammatory cytokine signaling pathways probed by measurements of extracellular acidification rate

Charles M. Roth, Rochelle L. Kohen, S. Patrick Walton, Martin L. Yarmush

Research output: Contribution to journalArticle

  • 10 Citations

Abstract

There is a growing interest in the mechanisms of how cells integrate the multitude of signals that emanate during inflammatory stimuli, such as the hepatic acute phase response to burn or trauma. We have used measurements of extracellular acidification rate (ECAR) of HepG2 cells cultured on microporous membranes to probe the coupling between signaling pathways for gp130 family cytokines (interleukin-6, oncostatin M) and IL-1, each of which is considered to play a significant role in the hepatic acute phase response. We found that brief (30 min or less) exposure to any of these cytokines desensitized the HepG2 cells to subsequent exposure with the same cytokine. Furthermore, we found that this property serves as a probe of the coupling of signaling pathways: exposure to IL-1 did not desensitize the cells to exposure to OSM and vice versa. However, cells exposed to IL-6 with soluble gp80, which together share with OSM the use of gp130 as a signal transducing receptor, were subsequently unable to respond to OSM, and vice versa. Simultaneous exposure of cells to moderate concentrations (near their respective EC50 values) of both IL-1 and OSM resulted in synergistic effects on the ECAR, but simultaneous exposure to saturating concentrations of IL-1 and OSM resulted in a response that tracked that of OSM alone. These results suggest that the signaling pathways of IL-1 and OSM may be simultaneously activated in HepG2 cells under moderate inflammatory cytokine challenge but that the cells must prioritize their response under extreme cytokine challenges.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalBiophysical Chemistry
Volume89
Issue number1
DOIs
StatePublished - Jan 31 2001
Externally publishedYes

Profile

Interleukin-1
Cytokines
cells
Hep G2 Cells
Fluorinated Steroids
Acute-Phase Reaction
Interleukin-6
Liver
Buccal Administration
phase response
probes
Oncostatin M
Membranes
Wounds and Injuries
Bronchiolo-Alveolar Adenocarcinoma
interleukins
cultured cells
stimuli
membranes

Keywords

  • Acute phase response
  • Desensitization
  • Dose response mechanisms
  • Microphysiometer
  • Signaling dynamics

ASJC Scopus subject areas

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Biophysics

Cite this

Coupling of inflammatory cytokine signaling pathways probed by measurements of extracellular acidification rate. / Roth, Charles M.; Kohen, Rochelle L.; Walton, S. Patrick; Yarmush, Martin L.

In: Biophysical Chemistry, Vol. 89, No. 1, 31.01.2001, p. 1-12.

Research output: Contribution to journalArticle

Roth, Charles M.; Kohen, Rochelle L.; Walton, S. Patrick; Yarmush, Martin L. / Coupling of inflammatory cytokine signaling pathways probed by measurements of extracellular acidification rate.

In: Biophysical Chemistry, Vol. 89, No. 1, 31.01.2001, p. 1-12.

Research output: Contribution to journalArticle

@article{6952ce6da3334cfeab040b8793b01142,
title = "Coupling of inflammatory cytokine signaling pathways probed by measurements of extracellular acidification rate",
abstract = "There is a growing interest in the mechanisms of how cells integrate the multitude of signals that emanate during inflammatory stimuli, such as the hepatic acute phase response to burn or trauma. We have used measurements of extracellular acidification rate (ECAR) of HepG2 cells cultured on microporous membranes to probe the coupling between signaling pathways for gp130 family cytokines (interleukin-6, oncostatin M) and IL-1, each of which is considered to play a significant role in the hepatic acute phase response. We found that brief (30 min or less) exposure to any of these cytokines desensitized the HepG2 cells to subsequent exposure with the same cytokine. Furthermore, we found that this property serves as a probe of the coupling of signaling pathways: exposure to IL-1 did not desensitize the cells to exposure to OSM and vice versa. However, cells exposed to IL-6 with soluble gp80, which together share with OSM the use of gp130 as a signal transducing receptor, were subsequently unable to respond to OSM, and vice versa. Simultaneous exposure of cells to moderate concentrations (near their respective EC50 values) of both IL-1 and OSM resulted in synergistic effects on the ECAR, but simultaneous exposure to saturating concentrations of IL-1 and OSM resulted in a response that tracked that of OSM alone. These results suggest that the signaling pathways of IL-1 and OSM may be simultaneously activated in HepG2 cells under moderate inflammatory cytokine challenge but that the cells must prioritize their response under extreme cytokine challenges.",
keywords = "Acute phase response, Desensitization, Dose response mechanisms, Microphysiometer, Signaling dynamics",
author = "Roth, {Charles M.} and Kohen, {Rochelle L.} and Walton, {S. Patrick} and Yarmush, {Martin L.}",
year = "2001",
month = "1",
doi = "10.1016/S0301-4622(00)00212-X",
volume = "89",
pages = "1--12",
journal = "Biophysical Chemistry",
issn = "0301-4622",
publisher = "Elsevier",
number = "1",

}

TY - JOUR

T1 - Coupling of inflammatory cytokine signaling pathways probed by measurements of extracellular acidification rate

AU - Roth,Charles M.

AU - Kohen,Rochelle L.

AU - Walton,S. Patrick

AU - Yarmush,Martin L.

PY - 2001/1/31

Y1 - 2001/1/31

N2 - There is a growing interest in the mechanisms of how cells integrate the multitude of signals that emanate during inflammatory stimuli, such as the hepatic acute phase response to burn or trauma. We have used measurements of extracellular acidification rate (ECAR) of HepG2 cells cultured on microporous membranes to probe the coupling between signaling pathways for gp130 family cytokines (interleukin-6, oncostatin M) and IL-1, each of which is considered to play a significant role in the hepatic acute phase response. We found that brief (30 min or less) exposure to any of these cytokines desensitized the HepG2 cells to subsequent exposure with the same cytokine. Furthermore, we found that this property serves as a probe of the coupling of signaling pathways: exposure to IL-1 did not desensitize the cells to exposure to OSM and vice versa. However, cells exposed to IL-6 with soluble gp80, which together share with OSM the use of gp130 as a signal transducing receptor, were subsequently unable to respond to OSM, and vice versa. Simultaneous exposure of cells to moderate concentrations (near their respective EC50 values) of both IL-1 and OSM resulted in synergistic effects on the ECAR, but simultaneous exposure to saturating concentrations of IL-1 and OSM resulted in a response that tracked that of OSM alone. These results suggest that the signaling pathways of IL-1 and OSM may be simultaneously activated in HepG2 cells under moderate inflammatory cytokine challenge but that the cells must prioritize their response under extreme cytokine challenges.

AB - There is a growing interest in the mechanisms of how cells integrate the multitude of signals that emanate during inflammatory stimuli, such as the hepatic acute phase response to burn or trauma. We have used measurements of extracellular acidification rate (ECAR) of HepG2 cells cultured on microporous membranes to probe the coupling between signaling pathways for gp130 family cytokines (interleukin-6, oncostatin M) and IL-1, each of which is considered to play a significant role in the hepatic acute phase response. We found that brief (30 min or less) exposure to any of these cytokines desensitized the HepG2 cells to subsequent exposure with the same cytokine. Furthermore, we found that this property serves as a probe of the coupling of signaling pathways: exposure to IL-1 did not desensitize the cells to exposure to OSM and vice versa. However, cells exposed to IL-6 with soluble gp80, which together share with OSM the use of gp130 as a signal transducing receptor, were subsequently unable to respond to OSM, and vice versa. Simultaneous exposure of cells to moderate concentrations (near their respective EC50 values) of both IL-1 and OSM resulted in synergistic effects on the ECAR, but simultaneous exposure to saturating concentrations of IL-1 and OSM resulted in a response that tracked that of OSM alone. These results suggest that the signaling pathways of IL-1 and OSM may be simultaneously activated in HepG2 cells under moderate inflammatory cytokine challenge but that the cells must prioritize their response under extreme cytokine challenges.

KW - Acute phase response

KW - Desensitization

KW - Dose response mechanisms

KW - Microphysiometer

KW - Signaling dynamics

UR - http://www.scopus.com/inward/record.url?scp=0035977654&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035977654&partnerID=8YFLogxK

U2 - 10.1016/S0301-4622(00)00212-X

DO - 10.1016/S0301-4622(00)00212-X

M3 - Article

VL - 89

SP - 1

EP - 12

JO - Biophysical Chemistry

T2 - Biophysical Chemistry

JF - Biophysical Chemistry

SN - 0301-4622

IS - 1

ER -