PMID- 16835063
OWN - NLM
STAT- MEDLINE
DCOM- 20061102
LR  - 20181201
IS  - 0091-6765 (Print)
IS  - 1552-9924 (Electronic)
IS  - 0091-6765 (Linking)
VI  - 114
IP  - 7
DP  - 2006 Jul
TI  - Uncoupling of ATP-mediated calcium signaling and dysregulated interleukin-6 
      secretion in dendritic cells by nanomolar thimerosal.
PG  - 1083-91
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.
FAU - Goth, Samuel R
AU  - Goth SR
AD  - National Institute of Environmental Health Sciences Center for Children's 
      Environmental Health, and Department of Veterinary Molecular Biosciences, 
      University of California-Davis, Davis, California, USA.
FAU - Chu, Ruth A
AU  - Chu RA
FAU - Gregg, Jeffrey P
AU  - Gregg JP
FAU - Cherednichenko, Gennady
AU  - Cherednichenko G
FAU - Pessah, Isaac N
AU  - Pessah IN
LA  - eng
GR  - F32 ES005707/ES/NIEHS NIH HHS/United States
GR  - P01 ES011269/ES/NIEHS NIH HHS/United States
GR  - C06 RR-12088-01/RR/NCRR NIH HHS/United States
GR  - P30 ES005707/ES/NIEHS NIH HHS/United States
GR  - ES05707/ES/NIEHS NIH HHS/United States
GR  - P01 ES11269/ES/NIEHS NIH HHS/United States
GR  - C06 RR012088/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Environ Health Perspect
JT  - Environmental health perspectives
JID - 0330411
RN  - 0 (Biomarkers)
RN  - 0 (Interleukin-6)
RN  - 2225PI3MOV (Thimerosal)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
SB  - IM
MH  - Adenosine Triphosphate/*pharmacology
MH  - Animals
MH  - Biomarkers
MH  - Calcium Signaling/*drug effects
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Dendritic Cells/*drug effects/*metabolism
MH  - Female
MH  - Gene Expression Regulation
MH  - Interleukin-6/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Thimerosal/*pharmacology
PMC - PMC1513334
EDAT- 2006/07/13 09:00
MHDA- 2006/11/03 09:00
PMCR- 2006/07/01
CRDT- 2006/07/13 09:00
PHST- 2006/07/13 09:00 [pubmed]
PHST- 2006/11/03 09:00 [medline]
PHST- 2006/07/13 09:00 [entrez]
PHST- 2006/07/01 00:00 [pmc-release]
AID - ehp0114-001083 [pii]
AID - 10.1289/ehp.8881 [doi]
PST - ppublish
SO  - Environ Health Perspect. 2006 Jul;114(7):1083-91. doi: 10.1289/ehp.8881.