TY - JOUR
T1 - Convergence of alpha 7 nicotinic acetylcholine receptor-activated pathways for anti-apoptosis and anti-inflammation
T2 - Central role for JAK2 activation of STAT3 and NF-κB
AU - Marrero, Mario B.
AU - Bencherif, Merouane
PY - 2009/2/23
Y1 - 2009/2/23
N2 - Our laboratories have previously identified the α7 nAChR-JAK2 pathway as playing a central role in nicotine-induced neuroprotection. We have also reported that the angiotensin II (Ang II) AT2 receptor induced activation of SHP-1 induces the tyrosine dephosphorylation of JAK2 that results in a complete neutralization of the α7 nAChR-JAK2 pro-survival cascade. In this study, we investigated the effects of inhibiting the α7 nAChR-JAK2 pro-survival cascade on the nicotine-induced production of the survival factor Bcl-2 and the transcriptional activation of NF-κB, AP-1, STAT1, STAT3, and STAT5. We report that nicotine induced the production of Bcl-2 and increased the transcriptional activation of NF-κB, AP-1, STAT1, and STAT3, and with the exception of AP-1, the other transcription factors (NF-κB, STAT1, and STAT3) were significantly reduced by JAK2 inhibition. We also demonstrate that, via transfection of either Bcl-2 antisense or NF-κB, STAT1 and STAT3 transcription factor decoys oligodeoxyribonucleotides into PC12 cells, nicotine induces its neuroprotection in PC12 cells via activation of the α7 nAChR-JAK2-(NF-κB; STAT3)-Bcl-2 pro-survival pathway. Finally, the neuroprotective nicotine-induced production of Bcl-2 appears to fully counteract the Aβ (1-42)-induced apoptosis of PC12 cells by blocking Aβ (1-42)-induced mitochondrial release of cytosolic cytochrome C.
AB - Our laboratories have previously identified the α7 nAChR-JAK2 pathway as playing a central role in nicotine-induced neuroprotection. We have also reported that the angiotensin II (Ang II) AT2 receptor induced activation of SHP-1 induces the tyrosine dephosphorylation of JAK2 that results in a complete neutralization of the α7 nAChR-JAK2 pro-survival cascade. In this study, we investigated the effects of inhibiting the α7 nAChR-JAK2 pro-survival cascade on the nicotine-induced production of the survival factor Bcl-2 and the transcriptional activation of NF-κB, AP-1, STAT1, STAT3, and STAT5. We report that nicotine induced the production of Bcl-2 and increased the transcriptional activation of NF-κB, AP-1, STAT1, and STAT3, and with the exception of AP-1, the other transcription factors (NF-κB, STAT1, and STAT3) were significantly reduced by JAK2 inhibition. We also demonstrate that, via transfection of either Bcl-2 antisense or NF-κB, STAT1 and STAT3 transcription factor decoys oligodeoxyribonucleotides into PC12 cells, nicotine induces its neuroprotection in PC12 cells via activation of the α7 nAChR-JAK2-(NF-κB; STAT3)-Bcl-2 pro-survival pathway. Finally, the neuroprotective nicotine-induced production of Bcl-2 appears to fully counteract the Aβ (1-42)-induced apoptosis of PC12 cells by blocking Aβ (1-42)-induced mitochondrial release of cytosolic cytochrome C.
KW - Apoptosis
KW - Inflammation
KW - Janus kinase
KW - NFκB
KW - Nicotinic receptor
KW - STAT3
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UR - http://www.scopus.com/inward/citedby.url?scp=59649084358&partnerID=8YFLogxK
U2 - 10.1016/j.brainres.2008.11.053
DO - 10.1016/j.brainres.2008.11.053
M3 - Article
C2 - 19063868
AN - SCOPUS:59649084358
SN - 0006-8993
VL - 1256
SP - 1
EP - 7
JO - Brain Research
JF - Brain Research
ER -