PMID- 18433816
OWN - NLM
STAT- MEDLINE
DCOM- 20080804
LR  - 20211020
IS  - 0041-008X (Print)
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Linking)
VI  - 229
IP  - 2
DP  - 2008 Jun 1
TI  - Reduction of myeloid suppressor cell derived nitric oxide provides a mechanistic 
      basis of lead enhancement of alloreactive CD4(+) T cell proliferation.
PG  - 135-45
LID - 10.1016/j.taap.2007.12.011 [doi]
AB  - The persistent environmental toxicant and immunomodulator, lead (Pb), has been 
      proposed to directly target CD4(+) T cells. However, our studies suggest that 
      CD4(+) T cells are an important functional, yet indirect target. In order to 
      identify the direct target of Pb in the immune system and the potential mechanism 
      of Pb-induced immunotoxicity, myeloid suppressor cells (MSCs) were evaluated for 
      their ability to modulate CD4(+) T cell proliferation after Pb exposure. Myeloid 
      suppressor cells regulate the adaptive immune response, in part, by inhibiting 
      the proliferation of CD4(+) T cells. It is thought that the mechanism of 
      MSC-dependent regulation involves the release of the bioactive gas, nitric oxide 
      (NO), blocking cell signaling cascades downstream of the IL-2 receptor and thus 
      preventing T cells from entering cell-cycle. In mixed lymphocyte culture (MLC), 
      increasing numbers of MSCs suppressed T cell proliferation in a dose-dependent 
      manner, and this suppression is strikingly abrogated with 5 microM lead (Pb) 
      treatment. The Pb-sensitive MSC population is CD11b(+), GR1(+)and CD11c(-) and 
      thus phenotypically consistent with MSCs described in other literature. 
      Inhibition of NO-synthase (NOS), the enzyme responsible for the production of NO, 
      enhanced alloreactive T cell proliferation in MLC. Moreover, Pb attenuated NO 
      production in MLC, and exogenous replacement of NO restored suppression in the 
      presence of Pb. Significantly, MSC from iNOS-/- mice were unable to suppress T 
      cell proliferation. An MSC-derived cell line (MSC-1) also suppressed T cell 
      proliferation in MLC, and Pb disrupted this suppression by attenuating NO 
      production. Additionally, Pb disrupted NO production in MSC-1 cells in response 
      to treatment with interferon-gamma (IFN-gamma) and LPS or in response to 
      concanavalin A-stimulated splenocytes. However, neither the abundance of protein 
      nor levels of mRNA for the inducible isoform of NOS (iNOS) were altered with Pb 
      treatment. Taken together these data suggest that Pb abrogates an MSC-dependent 
      suppression of alloreactive T cell proliferation by inhibiting the function, but 
      not the expression of iNOS.
FAU - Farrer, David G
AU  - Farrer DG
AD  - Department of Environmental Medicine, School of Medicine and Dentistry, 
      University of Rochester Rochester, NY, USA.
FAU - Hueber, Sara
AU  - Hueber S
FAU - Laiosa, Michael D
AU  - Laiosa MD
FAU - Eckles, Kevin G
AU  - Eckles KG
FAU - McCabe, Michael J Jr
AU  - McCabe MJ Jr
LA  - eng
GR  - T32 ES07026/ES/NIEHS NIH HHS/United States
GR  - P30 ES001247/ES/NIEHS NIH HHS/United States
GR  - R01 ES012403/ES/NIEHS NIH HHS/United States
GR  - P30 ES01247/ES/NIEHS NIH HHS/United States
GR  - T32 ES007026/ES/NIEHS NIH HHS/United States
GR  - R01 ES012403-04/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20080422
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (DNA Primers)
RN  - 0 (Lipopolysaccharides)
RN  - 2P299V784P (Lead)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - CD4-Positive T-Lymphocytes/cytology/*drug effects
MH  - Cell Line
MH  - Cell Proliferation/*drug effects
MH  - DNA Primers
MH  - Interferon-gamma/pharmacology
MH  - Lead/*toxicity
MH  - Lipopolysaccharides/pharmacology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Nitric Oxide/*antagonists & inhibitors/physiology
MH  - Nitric Oxide Synthase Type II/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
PMC - PMC2526553
MID - NIHMS54339
EDAT- 2008/04/25 09:00
MHDA- 2008/08/05 09:00
PMCR- 2009/06/01
CRDT- 2008/04/25 09:00
PHST- 2007/09/17 00:00 [received]
PHST- 2007/12/05 00:00 [revised]
PHST- 2007/12/07 00:00 [accepted]
PHST- 2008/04/25 09:00 [pubmed]
PHST- 2008/08/05 09:00 [medline]
PHST- 2008/04/25 09:00 [entrez]
PHST- 2009/06/01 00:00 [pmc-release]
AID - S0041-008X(07)00562-5 [pii]
AID - 10.1016/j.taap.2007.12.011 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2008 Jun 1;229(2):135-45. doi: 
      10.1016/j.taap.2007.12.011. Epub 2008 Apr 22.