PMID- 19228389
OWN - NLM
STAT- MEDLINE
DCOM- 20090514
LR  - 20211020
IS  - 1742-2094 (Electronic)
IS  - 1742-2094 (Linking)
VI  - 6
DP  - 2009 Feb 19
TI  - Influence of HFE variants and cellular iron on monocyte chemoattractant 
      protein-1.
PG  - 6
LID - 10.1186/1742-2094-6-6 [doi]
AB  - BACKGROUND: Polymorphisms in the MHC class 1-like gene known as HFE have been 
      proposed as genetic modifiers of neurodegenerative diseases that include 
      neuroinflammation as part of the disease process. Variants of HFE are relatively 
      common in the general population and are most commonly associated with iron 
      overload, but can promote subclinical cellular iron loading even in the absence 
      of clinically identified disease. The effects of the variants as well as the 
      resulting cellular iron dyshomeostasis potentially impact a number of 
      disease-associated pathways. We tested the hypothesis that the two most common 
      HFE variants, H63D and C282Y, would affect cellular secretion of cytokines and 
      trophic factors. METHODS: We screened a panel of cytokines and trophic factors 
      using a multiplexed immunoassay in human neuroblastoma SH-SY5Y cells expressing 
      different variants of HFE. The influence of cellular iron secretion on the potent 
      chemokine monocyte chemoattractant protein-1 (MCP-1) was assessed using ferric 
      ammonium citrate and the iron chelator, desferroxamine. Additionally, an 
      antioxidant, Trolox, and an anti-inflammatory, minocycline, were tested for their 
      effects on MCP-1 secretion in the presence of HFE variants. RESULTS: Expression 
      of the HFE variants altered the labile iron pool in SH-SY5Y cells. Of the panel 
      of cytokines and trophic factors analyzed, only the release of MCP-1 was affected 
      by the HFE variants. We further examined the relationship between iron and MCP-1 
      and found MCP-1 secretion tightly associated with intracellular iron status. A 
      potential direct effect of HFE is considered because, despite having similar 
      levels of intracellular iron, the association between HFE genotype and MCP-1 
      expression was different for the H63D and C282Y HFE variants. Moreover, HFE 
      genotype was a factor in the effect of minocycline, a multifaceted antibiotic 
      used in treating a number of neurologic conditions associated with inflammation, 
      on MCP-1 secretion. CONCLUSION: Our results demonstrate that HFE polymorphisms 
      influence the synthesis and release of MCP-1. The mechanism of action involves 
      cellular iron status but it appears there could be additional influences such as 
      ER stress. Finally, these data demonstrate a pharmacogenetic effect of HFE 
      polymorphisms on the ability of minocycline to inhibit MCP-1 secretion.
FAU - Mitchell, Ryan M
AU  - Mitchell RM
AD  - George M Leader Family Laboratory, Department of Neurosurgery, Pennsylvania State 
      University College of Medicine/Milton S Hershey Medical Center, Hershey, PA 
      17033, USA. rmm311@psu.edu
FAU - Lee, Sang Y
AU  - Lee SY
FAU - Randazzo, William T
AU  - Randazzo WT
FAU - Simmons, Zachary
AU  - Simmons Z
FAU - Connor, James R
AU  - Connor JR
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090219
PL  - England
TA  - J Neuroinflammation
JT  - Journal of neuroinflammation
JID - 101222974
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Antioxidants)
RN  - 0 (CCL2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Chromans)
RN  - 0 (Ferric Compounds)
RN  - 0 (HFE protein, human)
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (Hemochromatosis Protein)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Iron Chelating Agents)
RN  - 0 (Membrane Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (Quaternary Ammonium Compounds)
RN  - 0 (RNA, Messenger)
RN  - E1UOL152H7 (Iron)
RN  - FYY3R43WGO (Minocycline)
RN  - J06Y7MXW4D (Deferoxamine)
RN  - S18UL9710X (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid)
RN  - UVP74NG1C5 (ferric ammonium citrate)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents/pharmacology
MH  - Antioxidants/pharmacology
MH  - Cell Line, Tumor
MH  - Chemokine CCL2/*metabolism
MH  - Chromans/pharmacology
MH  - Deferoxamine/pharmacology
MH  - Ferric Compounds/metabolism
MH  - Gene Expression
MH  - Heat-Shock Proteins/metabolism
MH  - Hemochromatosis Protein
MH  - Histocompatibility Antigens Class I/*genetics/*metabolism
MH  - Humans
MH  - Iron/*metabolism
MH  - Iron Chelating Agents/pharmacology
MH  - Membrane Proteins/*genetics/*metabolism
MH  - Mice
MH  - Microglia/drug effects/metabolism
MH  - Minocycline/pharmacology
MH  - NF-kappa B/metabolism
MH  - Neurons/drug effects/*metabolism
MH  - *Polymorphism, Single Nucleotide
MH  - Quaternary Ammonium Compounds/metabolism
MH  - RNA, Messenger/metabolism
PMC - PMC2656486
EDAT- 2009/02/21 09:00
MHDA- 2009/05/15 09:00
PMCR- 2009/02/19
CRDT- 2009/02/21 09:00
PHST- 2008/08/15 00:00 [received]
PHST- 2009/02/19 00:00 [accepted]
PHST- 2009/02/21 09:00 [entrez]
PHST- 2009/02/21 09:00 [pubmed]
PHST- 2009/05/15 09:00 [medline]
PHST- 2009/02/19 00:00 [pmc-release]
AID - 1742-2094-6-6 [pii]
AID - 10.1186/1742-2094-6-6 [doi]
PST - epublish
SO  - J Neuroinflammation. 2009 Feb 19;6:6. doi: 10.1186/1742-2094-6-6.