PMID- 23699531
OWN - NLM
STAT- MEDLINE
DCOM- 20130809
LR  - 20220409
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 33
IP  - 21
DP  - 2013 May 22
TI  - Progranulin does not bind tumor necrosis factor (TNF) receptors and is not a 
      direct regulator of TNF-dependent signaling or bioactivity in immune or neuronal 
      cells.
PG  - 9202-13
LID - 10.1523/JNEUROSCI.5336-12.2013 [doi]
AB  - Progranulin (PGRN) is a secreted glycoprotein expressed in neurons and glia that 
      is implicated in neuronal survival on the basis that mutations in the GRN gene 
      causing haploinsufficiency result in a familial form of frontotemporal dementia 
      (FTD). Recently, a direct interaction between PGRN and tumor necrosis factor 
      receptors (TNFR I/II) was reported and proposed to be a mechanism by which PGRN 
      exerts anti-inflammatory activity, raising the possibility that aberrant 
      PGRN-TNFR interactions underlie the molecular basis for neuroinflammation in 
      frontotemporal lobar degeneration pathogenesis. Here, we report that we find no 
      evidence for a direct physical or functional interaction between PGRN and TNFRs. 
      Using coimmunoprecipitation and surface plasmon resonance (SPR) we replicated the 
      interaction between PGRN and sortilin and that between TNF and TNFRI/II, but not 
      the interaction between PGRN and TNFRs. Recombinant PGRN or transfection of a 
      cDNA encoding PGRN did not antagonize TNF-dependent NFkappaB, Akt, and Erk1/2 pathway 
      activation; inflammatory gene expression; or secretion of inflammatory factors in 
      BV2 microglia and bone marrow-derived macrophages (BMDMs). Moreover, PGRN did not 
      antagonize TNF-induced cytotoxicity on dopaminergic neuroblastoma cells. Last, 
      co-addition or pre-incubation with various N- or C-terminal-tagged recombinant 
      PGRNs did not alter lipopolysaccharide-induced inflammatory gene expression or 
      cytokine secretion in any cell type examined, including BMDMs from Grn+/- or 
      Grn-/- mice. Therefore, the neuroinflammatory phenotype associated with PGRN 
      deficiency in the CNS is not a direct consequence of the loss of TNF antagonism 
      by PGRN, but may be a secondary response by glia to disrupted interactions 
      between PGRN and Sortilin and/or other binding partners yet to be identified.
FAU - Chen, Xi
AU  - Chen X
AD  - Department of Physiology and Department of Pharmacology, Emory University, School 
      of Medicine, Atlanta, Georgia 30322, USA.
FAU - Chang, Jianjun
AU  - Chang J
FAU - Deng, Qiudong
AU  - Deng Q
FAU - Xu, Jie
AU  - Xu J
FAU - Nguyen, Thi A
AU  - Nguyen TA
FAU - Martens, Lauren H
AU  - Martens LH
FAU - Cenik, Basar
AU  - Cenik B
FAU - Taylor, Georgia
AU  - Taylor G
FAU - Hudson, Kathryn F
AU  - Hudson KF
FAU - Chung, Jaegwon
AU  - Chung J
FAU - Yu, Kimberley
AU  - Yu K
FAU - Yu, Phillip
AU  - Yu P
FAU - Herz, Joachim
AU  - Herz J
FAU - Farese, Robert V Jr
AU  - Farese RV Jr
FAU - Kukar, Thomas
AU  - Kukar T
FAU - Tansey, Malu G
AU  - Tansey MG
LA  - eng
GR  - P50 AG023501/AG/NIA NIH HHS/United States
GR  - P30 DK063720/DK/NIDDK NIH HHS/United States
GR  - P50 AG016574/AG/NIA NIH HHS/United States
GR  - R01 NS049433/NS/NINDS NIH HHS/United States
GR  - 5P50AG016574-14/AG/NIA NIH HHS/United States
GR  - NIH-HL20948/HL/NHLBI NIH HHS/United States
GR  - R00 AG032362/AG/NIA NIH HHS/United States
GR  - R37 HL063762/HL/NHLBI NIH HHS/United States
GR  - NIH-NINDS 5RO1NS049433-05/NS/NINDS NIH HHS/United States
GR  - P01 HL020948/HL/NHLBI NIH HHS/United States
GR  - HL63762/HL/NHLBI NIH HHS/United States
GR  - R01 HL063762/HL/NHLBI NIH HHS/United States
GR  - NIH-NIA 4R00AG032362-03/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Adaptor Proteins, Vesicular Transport)
RN  - 0 (Culture Media, Conditioned)
RN  - 0 (Cytokines)
RN  - 0 (Granulins)
RN  - 0 (Grn protein, mouse)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Isoquinolines)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NF-kappa B)
RN  - 0 (Progranulins)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (Recombinant Proteins)
RN  - 9654F8OVKE (lucifer yellow)
RN  - Z020Y8WIJ4 (sortilin)
SB  - IM
MH  - Adaptor Proteins, Vesicular Transport/metabolism
MH  - Analysis of Variance
MH  - Animals
MH  - Cell Line
MH  - Cell Proliferation/drug effects
MH  - Culture Media, Conditioned/pharmacology
MH  - Cytokines/*metabolism
MH  - Gene Expression Regulation/drug effects/genetics/*immunology
MH  - Granulins
MH  - Humans
MH  - Immunoprecipitation
MH  - Intercellular Signaling Peptides and Proteins/deficiency/genetics/*metabolism
MH  - Isoquinolines/metabolism
MH  - Lipopolysaccharides/pharmacology
MH  - MAP Kinase Signaling System/drug effects/immunology
MH  - Macrophages/drug effects/immunology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Microglia/drug effects/metabolism
MH  - NF-kappa B/metabolism
MH  - Progranulins
MH  - Protein Binding/genetics
MH  - Receptors, Tumor Necrosis Factor/genetics/*metabolism
MH  - Recombinant Proteins/pharmacology
MH  - Signal Transduction/drug effects/*physiology
MH  - Surface Plasmon Resonance
MH  - Transfection
PMC - PMC3707136
MID - NIHMS483492
EDAT- 2013/05/24 06:00
MHDA- 2013/08/10 06:00
PMCR- 2013/11/22
CRDT- 2013/05/24 06:00
PHST- 2013/05/24 06:00 [entrez]
PHST- 2013/05/24 06:00 [pubmed]
PHST- 2013/08/10 06:00 [medline]
PHST- 2013/11/22 00:00 [pmc-release]
AID - 33/21/9202 [pii]
AID - 5336-12 [pii]
AID - 10.1523/JNEUROSCI.5336-12.2013 [doi]
PST - ppublish
SO  - J Neurosci. 2013 May 22;33(21):9202-13. doi: 10.1523/JNEUROSCI.5336-12.2013.