MCP-1 involvement in glial differentiation of neuroprogenitor cells through APP signaling.
Previously it has been reported that neural stem cells undergoing apoptotic stress have increased levels of amyloid precursor protein (APP) and increased APP expression results in glial differentiation. APP activity was also shown to be required for staurosporine-induced glial differentiation of neuroprogenitor cells. Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that is expressed early during inflammation. The binding of MCP-1 to its chemokine receptor induces expression of novel transcription factor MCP-1-induced protein (MCPIP). MCPIP expression subsequently leads to cell death. Previous studies have shown that pro-apoptotic factors have the ability to induce neural differentiation. Therefore, we investigated if MCPIP expression leads to differentiation of NT2 neuroprogenitor cells. Results showed that MCPIP expression increased glial fibrillary acid protein (GFAP) expression and also caused distinct morphological changes, both indicative of glial differentiation. Similar results were observed with MCP-1 treatment. Interestingly, APP expression decreased in response to MCPIP. Instead, we found APP activity regulates expression of both MCP-1 and MCPIP. Furthermore, inhibition of either p38 MAPK or JAK signaling pathways significantly reduced APP's effect on MCP-1 and MCPIP. These data demonstrates the role APP has in glial differentiation of NT2 cells through MCP-1/MCPIP signaling. It is possible that increased APP expression after CNS injury could play a role in MCP-1 production, possibly promoting astrocyte activation at injured site.
Vrotsos
Emmanuel George
EG
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816-2364, USA.
Kolattukudy
Pappachan E
PE
Sugaya
Kiminobu
K
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D009457:Neuroglia / Q000166:cytology / Q000502:physiology*; D010766:Phosphorylation; D058255:Protease Nexins; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012260:Ribonucleases; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D005904:Glial Fibrillary Acidic Protein; D058255:Protease Nexins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014157:Transcription Factors; D053612:Janus Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D012260:Ribonucleases; C510646:ZC3H12A protein, human