Activation of the JAK-STAT signaling pathway in the rat basilar artery after subarachnoid hemorrhage.
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) is one of the most important signaling pathways transducing signals from the cell surface in response to cytokines. Subarachnoid hemorrhage (SAH) produces cytokines in the CSF. We investigated whether this signaling pathway is activated in the rat basilar artery after SAH by cytokines. In a rat single-hemorrhage model of SAH, basilar arteries and CSF were obtained until 7 days after SAH. The concentration of interleukin-6 (IL-6) in CSF was measured by ELISA. Western blot analysis with JAK1, phosphospecific-JAK1, STAT3, phosphospecific STAT3 at Tyr705 and Ser727, cyclooxygenase-2 (COX-2), and actin antibodies was performed in basilar artery. The expressions of STAT3, phosphospecific STAT3 at Tyr705 and Ser727, and COX-2 in basilar artery were examined by immunohistochemical studies. The concentration of IL-6 immediately increased after SAH and Western blot analysis revealed that JAK1 was phosphorylated within 2 h, accompanied by phosphorylation of STAT3 at Tyr705, extending to Ser727 at days 1-2. Immunohistochemistry revealed phosphorylation of STAT3 to occur in endothelial and smooth muscle cells of the basilar artery. In addition, intracisternal injection of IL-6 by itself significantly increased phosphorylation of STAT3 at Tyr705 and Ser727. Expression of COX-2 was also upregulated in endothelial cells of the basilar artery. These results indicate that SAH produces the proinflammatory cytokine IL-6 in the CSF, which activates the JAK-STAT signaling pathway in the basilar artery and induces transcription of immediate early genes.
Osuka
Koji
K
Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Watanabe
Yasuo
Y
Yamauchi
Katsuaki
K
Nakazawa
Ayami
A
Usuda
Nobuteru
N
Tokuda
Masaaki
M
Yoshida
Jun
J
D000818:Animals; D001488:Basilar Artery / Q000503:physiopathology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000134:cerebrospinal fluid* / Q000494:pharmacology; D053613:Janus Kinase 1; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013345:Subarachnoid Hemorrhage / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*
D016207:Cytokines; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D010768:Phosphoserine; D019000:Phosphotyrosine; D051546:Cyclooxygenase 2; D011505:Protein-Tyrosine Kinases; C507906:Jak1 protein, rat; D053613:Janus Kinase 1