Convergence of alpha 7 nicotinic acetylcholine receptor-activated pathways for anti-apoptosis and anti-inflammation: Central role for JAK2 activation of STAT3 and NF-κB

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.