Uncoupling of ATP-mediated calcium signaling and dysregulated interleukin-6 secretion in dendritic cells by nanomolar thimerosal

Samuel R. Goth, Ruth A. Chu, Jeffrey Gregg, Gennady Cherednichenko, Isaac N Pessah

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Dendritic cells (DCs), a rare cell type widely distributed in the soma, are potent antigen-presenting cells that initiate primary immune responses. DCs rely on intracellular redox state and calcium (Ca2+) signals for proper development and function, but the relationship between these two signaling systems is unclear. Thimerosal (THI) is a mercurial used to preserve vaccines and consumer products, and is used experimentally to induce Ca2+ release from microsomal stores. We tested adenosine triphosphate (ATP)-mediated Ca2+ responses of DCs transiently exposed to nanomolar THI. Transcriptional and immunocytochemical analyses show that murine myeloid immature DCs (IDCs) and mature DCs (MDCs) express inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR) Ca2+ channels, known targets of THI. IDCs express the RyR1 isoform in a punctate distribution that is densest near plasma membranes and within dendritic processes, whereas IP3Rs are more generally distributed. RyR1 positively and negatively regulates purinergic signaling because ryanodine (Ry) blockade a) recruited 80% more ATP responders, b) shortened ATP-mediated Ca2+ transients > 2-fold, and c) produced a delayed and persistent rise (≥ 2-fold) in baseline Ca2+. THI (100 nM, 5 min) recruited more ATP responders, shortened the ATP-mediated Ca2+ transient (≥ 1.4-fold), and produced a delayed rise (≥ 3-fold) in the Ca2+ baseline, mimicking Ry. THI and Ry, in combination, produced additive effects leading to uncoupling of IP3R and RyR1 signals. THI altered ATP-mediated interleukin-6 secretion, initially enhancing the rate of cytokine secretion but suppressing cytokine secretion overall in DCs. DCs are exquisitely sensitive to THI, with one mechanism involving the uncoupling of positive and negative regulation of Ca2+ signals contributed by RyR1.

Original languageEnglish (US)
Pages (from-to)1083-1091
Number of pages9
JournalEnvironmental Health Perspectives
Volume114
Issue number7
DOIs
StatePublished - Jul 2006

Fingerprint

Thimerosal
Calcium Signaling
secretion
Dendritic Cells
Ryanodine Receptor Calcium Release Channel
Interleukin-6
Adenosine Triphosphate
calcium
fold
Calcium
Ryanodine
vaccine
antigen
immune response
Cytokines
Inositol 1,4,5-Trisphosphate Receptors
membrane
Consumer products
plasma
Carisoprodol

Keywords

  • Calcium
  • Calcium channel
  • Dendritic cell
  • Ethyl mercury
  • Immunotoxicity
  • Interleukin-6
  • Organic mercury
  • Redox
  • Thimerosal

ASJC Scopus subject areas

  • Environmental Science(all)
  • Environmental Chemistry
  • Public Health, Environmental and Occupational Health

Cite this

Uncoupling of ATP-mediated calcium signaling and dysregulated interleukin-6 secretion in dendritic cells by nanomolar thimerosal. / Goth, Samuel R.; Chu, Ruth A.; Gregg, Jeffrey; Cherednichenko, Gennady; Pessah, Isaac N.

In: Environmental Health Perspectives, Vol. 114, No. 7, 07.2006, p. 1083-1091.

Research output: Contribution to journalArticle

@article{9121f699f6f446dc9b1c9f551dad2c88,
title = "Uncoupling of ATP-mediated calcium signaling and dysregulated interleukin-6 secretion in dendritic cells by nanomolar thimerosal",
abstract = "Dendritic cells (DCs), a rare cell type widely distributed in the soma, are potent antigen-presenting cells that initiate primary immune responses. DCs rely on intracellular redox state and calcium (Ca2+) signals for proper development and function, but the relationship between these two signaling systems is unclear. Thimerosal (THI) is a mercurial used to preserve vaccines and consumer products, and is used experimentally to induce Ca2+ release from microsomal stores. We tested adenosine triphosphate (ATP)-mediated Ca2+ responses of DCs transiently exposed to nanomolar THI. Transcriptional and immunocytochemical analyses show that murine myeloid immature DCs (IDCs) and mature DCs (MDCs) express inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR) Ca2+ channels, known targets of THI. IDCs express the RyR1 isoform in a punctate distribution that is densest near plasma membranes and within dendritic processes, whereas IP3Rs are more generally distributed. RyR1 positively and negatively regulates purinergic signaling because ryanodine (Ry) blockade a) recruited 80{\%} more ATP responders, b) shortened ATP-mediated Ca2+ transients > 2-fold, and c) produced a delayed and persistent rise (≥ 2-fold) in baseline Ca2+. THI (100 nM, 5 min) recruited more ATP responders, shortened the ATP-mediated Ca2+ transient (≥ 1.4-fold), and produced a delayed rise (≥ 3-fold) in the Ca2+ baseline, mimicking Ry. THI and Ry, in combination, produced additive effects leading to uncoupling of IP3R and RyR1 signals. THI altered ATP-mediated interleukin-6 secretion, initially enhancing the rate of cytokine secretion but suppressing cytokine secretion overall in DCs. DCs are exquisitely sensitive to THI, with one mechanism involving the uncoupling of positive and negative regulation of Ca2+ signals contributed by RyR1.",
keywords = "Calcium, Calcium channel, Dendritic cell, Ethyl mercury, Immunotoxicity, Interleukin-6, Organic mercury, Redox, Thimerosal",
author = "Goth, {Samuel R.} and Chu, {Ruth A.} and Jeffrey Gregg and Gennady Cherednichenko and Pessah, {Isaac N}",
year = "2006",
month = "7",
doi = "10.1289/ehp.8881",
language = "English (US)",
volume = "114",
pages = "1083--1091",
journal = "Environmental Health Perspectives",
issn = "0091-6765",
publisher = "Public Health Services, US Dept of Health and Human Services",
number = "7",

}

TY - JOUR

T1 - Uncoupling of ATP-mediated calcium signaling and dysregulated interleukin-6 secretion in dendritic cells by nanomolar thimerosal

AU - Goth, Samuel R.

AU - Chu, Ruth A.

AU - Gregg, Jeffrey

AU - Cherednichenko, Gennady

AU - Pessah, Isaac N

PY - 2006/7

Y1 - 2006/7

N2 - Dendritic cells (DCs), a rare cell type widely distributed in the soma, are potent antigen-presenting cells that initiate primary immune responses. DCs rely on intracellular redox state and calcium (Ca2+) signals for proper development and function, but the relationship between these two signaling systems is unclear. Thimerosal (THI) is a mercurial used to preserve vaccines and consumer products, and is used experimentally to induce Ca2+ release from microsomal stores. We tested adenosine triphosphate (ATP)-mediated Ca2+ responses of DCs transiently exposed to nanomolar THI. Transcriptional and immunocytochemical analyses show that murine myeloid immature DCs (IDCs) and mature DCs (MDCs) express inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR) Ca2+ channels, known targets of THI. IDCs express the RyR1 isoform in a punctate distribution that is densest near plasma membranes and within dendritic processes, whereas IP3Rs are more generally distributed. RyR1 positively and negatively regulates purinergic signaling because ryanodine (Ry) blockade a) recruited 80% more ATP responders, b) shortened ATP-mediated Ca2+ transients > 2-fold, and c) produced a delayed and persistent rise (≥ 2-fold) in baseline Ca2+. THI (100 nM, 5 min) recruited more ATP responders, shortened the ATP-mediated Ca2+ transient (≥ 1.4-fold), and produced a delayed rise (≥ 3-fold) in the Ca2+ baseline, mimicking Ry. THI and Ry, in combination, produced additive effects leading to uncoupling of IP3R and RyR1 signals. THI altered ATP-mediated interleukin-6 secretion, initially enhancing the rate of cytokine secretion but suppressing cytokine secretion overall in DCs. DCs are exquisitely sensitive to THI, with one mechanism involving the uncoupling of positive and negative regulation of Ca2+ signals contributed by RyR1.

AB - Dendritic cells (DCs), a rare cell type widely distributed in the soma, are potent antigen-presenting cells that initiate primary immune responses. DCs rely on intracellular redox state and calcium (Ca2+) signals for proper development and function, but the relationship between these two signaling systems is unclear. Thimerosal (THI) is a mercurial used to preserve vaccines and consumer products, and is used experimentally to induce Ca2+ release from microsomal stores. We tested adenosine triphosphate (ATP)-mediated Ca2+ responses of DCs transiently exposed to nanomolar THI. Transcriptional and immunocytochemical analyses show that murine myeloid immature DCs (IDCs) and mature DCs (MDCs) express inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR) Ca2+ channels, known targets of THI. IDCs express the RyR1 isoform in a punctate distribution that is densest near plasma membranes and within dendritic processes, whereas IP3Rs are more generally distributed. RyR1 positively and negatively regulates purinergic signaling because ryanodine (Ry) blockade a) recruited 80% more ATP responders, b) shortened ATP-mediated Ca2+ transients > 2-fold, and c) produced a delayed and persistent rise (≥ 2-fold) in baseline Ca2+. THI (100 nM, 5 min) recruited more ATP responders, shortened the ATP-mediated Ca2+ transient (≥ 1.4-fold), and produced a delayed rise (≥ 3-fold) in the Ca2+ baseline, mimicking Ry. THI and Ry, in combination, produced additive effects leading to uncoupling of IP3R and RyR1 signals. THI altered ATP-mediated interleukin-6 secretion, initially enhancing the rate of cytokine secretion but suppressing cytokine secretion overall in DCs. DCs are exquisitely sensitive to THI, with one mechanism involving the uncoupling of positive and negative regulation of Ca2+ signals contributed by RyR1.

KW - Calcium

KW - Calcium channel

KW - Dendritic cell

KW - Ethyl mercury

KW - Immunotoxicity

KW - Interleukin-6

KW - Organic mercury

KW - Redox

KW - Thimerosal

UR - http://www.scopus.com/inward/record.url?scp=33745791935&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33745791935&partnerID=8YFLogxK

U2 - 10.1289/ehp.8881

DO - 10.1289/ehp.8881

M3 - Article

C2 - 16835063

AN - SCOPUS:33745791935

VL - 114

SP - 1083

EP - 1091

JO - Environmental Health Perspectives

JF - Environmental Health Perspectives

SN - 0091-6765

IS - 7

ER -