PMID- 24826069
OWN - NLM
STAT- MEDLINE
DCOM- 20140930
LR  - 20220330
IS  - 1090-0535 (Electronic)
IS  - 1090-0535 (Linking)
VI  - 20
DP  - 2014
TI  - Retinal neuronal MCP-1 induced by AGEs stimulates TNF-alpha expression in rat 
      microglia via p38, ERK, and NF-kappaB pathways.
PG  - 616-28
AB  - PURPOSE: Retinal microglia can be activated by retinal neuronal monocyte 
      chemoattractant protein-1 (MCP-1) and play a pivotal role in early retinal 
      degeneration. The current study investigates the pathways via which retinal 
      neuronal MCP-1 stimulates tumor necrosis factor-alpha (TNF-alpha) expression in rat 
      microglia. METHODS: Primary rat retinal neurons and microglia were separated and 
      cocultured in a Transwell apparatus. The levels of TNF-alpha mRNA and soluble TNF-alpha 
      produced by the microglia in response to advanced glycation end product 
      (AGE)-induced retinal neuronal MCP-1 were measured with real-time PCR and 
      enzyme-linked immunosorbent assay (ELISA). The ability of neuronal MCP-1 to 
      stimulate microglia activation was examined by preexposing the retinal neurons to 
      AGEs and an MCP-1 antibody or by pretreating microglia with AGEs and siRNA 
      specific for CC-chemokine receptor 2 (CCR2) knockdowns. Additionally, we 
      investigated the effects of microglial activation on neuronal MCP-1-induced 
      nuclear factor-kappaB (NF-kappaB) activation and phosphorylation of mitogen-activated 
      protein kinases (MAPKs). RESULTS: Stimulation with AGEs significantly increased 
      the expression of TNF-alpha mRNA and soluble TNF-alpha in the microglial cells. Retinal 
      neurons that had been pretreated with AGEs and an MCP-1 antibody or microglia 
      that were CCR2 knockdowns displayed greatly reduced TNF-alpha secretion. Using 
      signaling pathway-specific inhibitors, we showed that blocking the p38, 
      extracellular signal-regulated kinase (ERK), and NF-kappaB signaling pathways 
      significantly reduced the expression of TNF-alpha by retinal neuronal 
      MCP-1-stimulated microglia. CONCLUSIONS: This study indicates that TNF-alpha was 
      released from the activated microglia induced by retinal neuronal MCP-1 via the 
      p38, ERK, and NF-kappaB pathways, but not c-Jun N-terminal kinase (JNK), which may be 
      an important finding in diabetic retinopathy pathogenesis.
FAU - Dong, Ning
AU  - Dong N
AD  - Department of Ophthalmology, Beijing Shijitan Hospital, Capital Medical 
      University, Beijing, People's Republic of China.
FAU - Chang, Libin
AU  - Chang L
AD  - Department of Ophthalmology, Beijing Shijitan Hospital, Capital Medical 
      University, Beijing, People's Republic of China.
FAU - Wang, Bingsong
AU  - Wang B
AD  - Department of Ophthalmology, Beijing Shijitan Hospital, Capital Medical 
      University, Beijing, People's Republic of China.
FAU - Chu, Liqun
AU  - Chu L
AD  - Department of Ophthalmology, Beijing Shijitan Hospital, Capital Medical 
      University, Beijing, People's Republic of China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140502
PL  - United States
TA  - Mol Vis
JT  - Molecular vision
JID - 9605351
RN  - 0 (Ccr2 protein, rat)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Glycation End Products, Advanced)
RN  - 0 (NF-kappa B)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, CCR2)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Chemokine CCL2/*metabolism
MH  - Extracellular Signal-Regulated MAP Kinases/*metabolism
MH  - Gene Knockdown Techniques
MH  - Glycation End Products, Advanced/*pharmacology
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - Microglia/drug effects/enzymology/*metabolism
MH  - NF-kappa B/*metabolism
MH  - Phosphorylation/drug effects
MH  - RNA, Small Interfering/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, CCR2/metabolism
MH  - Retinal Neurons/drug effects/*metabolism
MH  - Signal Transduction/drug effects
MH  - Tumor Necrosis Factor-alpha/*metabolism
MH  - p38 Mitogen-Activated Protein Kinases/*metabolism
PMC - PMC4016805
EDAT- 2014/05/16 06:00
MHDA- 2014/10/01 06:00
PMCR- 2014/01/01
CRDT- 2014/05/15 06:00
PHST- 2013/09/03 00:00 [received]
PHST- 2014/04/30 00:00 [accepted]
PHST- 2014/05/15 06:00 [entrez]
PHST- 2014/05/16 06:00 [pubmed]
PHST- 2014/10/01 06:00 [medline]
PHST- 2014/01/01 00:00 [pmc-release]
AID - 56 [pii]
PST - epublish
SO  - Mol Vis. 2014 May 2;20:616-28. eCollection 2014.