Reducing effect of IL-32α in the development of stroke through blocking of NF-κB, but enhancement of STAT3 pathways.
Neuroinflammation is important for the development of several neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and stroke. Since changes of cytokine level are critical for neuroinflammation in the brain, we investigated whether IL-32α overexpression could change neuroinflammation and, thus, affect stroke development. Middle cerebral artery occlusion (MCAO) induced development of ischemia, and ischemic neuronal cell death were reduced in IL-32α-overexpressing transgenic mice (IL-32α mice) brain through the decreased release of neuroinflammatory cytokines (IL-6, IL-1β, TNF-α) and activation of astrocytes, but enhancement of anti-neuroinflammatory cytokines (IL-10). Reactive oxygen species generation and lipid peroxidation as well as expression of inducible nitric oxide and cyclooxygenase-2 were also reduced in the IL-32α mice brain. Nuclear factor-kappa B (NF-κB), a critical transcriptional factor regulating neuroinflammation, was much lower, but activation of signal transducer and activator of transcription 3 (STAT3), which plays a crucial role in cell survival and proliferation, was much higher in IL-32α-overexpressing mice brain compared to those of wild-type mice brain. These results suggest that IL-32α can prevent cerebral ischemia damage via upregulation of anti-neuroinflammatory cytokine expression and STAT3 activation, but downregulation of neuroinflammatory cytokines and NF-κB activation.
College of Pharmacy and Medical Research Center, Chungbuk National University, 12 Gaeshin, Heungduk, Cheongju, Chungbuk, 361-763, Republic of Korea.
Chul Ju
CJ
Hwang
Hyung-Mun
HM
Yun
Yu Yeon
YY
Jung
Dong Hun
DH
Lee
Na Young
NY
Yoon
Hyun Ok
HO
Seo
Jin-Yi
JY
Han
Ki-Wan
KW
Oh
Dong Young
DY
Choi
Sang-Bae
SB
Han
Do Young
DY
Yoon
Jin Tae
JT
Hong
D000818:Animals; D007378:Interleukins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000096:biosynthesis*; D015398:Signal Transduction / Q000502:physiology*; D020521:Stroke / Q000378:metabolism* / Q000517:prevention & control*
D007378:Interleukins; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C569037:interleukin-32, mouse