title: Angiotensin II activates JAK2/STAT3 pathway and induces interleukin-6 production in cultured rat brainstem astrocytes.
abstract: We have shown that tyrosine kinases and mitogen-activated protein kinases mediate angiotensin II (Ang II) effects in cultured rat astrocytes. In this study, we investigated whether Ang II induces Janus kinase (JAK) 2, signal transducer and activators of transcription (STAT) 3 phosphorylation, and interleukin-6 (IL-6) secretion in cultured brainstem rat astrocytes. Ang II increased JAK2 phosphorylation in a time- and dose-dependent manner. Maximal phosphorylation of 1.7+/-0.4 fold above basal was observed at 15 min with 100 nM Ang II. Losartan (10 microM), an AT(1) receptor blocker, inhibited Ang II-mediated JAK2 phosphorylation, while 10 microM PD123319, an AT(2) receptor blocker, was ineffective. The JAK2 inhibitor, AG490 (50 microM), prevented Ang II JAK2 phosphorylation. Ang II also stimulated STAT3 in a concentration- and time-dependent manner. Maximal phosphorylation of 0.8+/-0.11 above basal was observed at 15 min with 100 nM Ang II. Treatment with AG490 reduced Ang II phosphorylation of STAT3 and Ang II-induced astrocyte growth suggesting that JAK2 is an upstream signal in these Ang II effects. Ang II also stimulated IL-6 secretion from brainstem astrocytes in a concentration- and time-dependent manner. Maximal IL-6 secretion of 0.7+/-0.2 above basal was observed with 100 nM Ang II after 48 h of treatment. Losartan decreased Ang II-induced IL-6 secretion while PD123319 was ineffective. Interestingly, AG490 reduced Ang II-stimulated IL-6 secretion. Our study showed for the first time that Ang II induced JAK2/STAT3 phosphorylation and IL-6 secretion through activation of the Ang II AT(1) receptor in brainstem astrocytes. In addition, Ang II stimulated IL-6 secretion and astrocyte growth through the JAK2 pathway in brainstem astrocytes. These results provide new insights into pro-inflammatory and mitogenic signaling mechanisms of Ang II in astrocytes.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, 3200 S. University Drive, Fort Lauderdale, FL 33328, USA.
authors.forename: Umadevi
authors.initials: U
authors.lastname: Kandalam
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Clark
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D001933:Brain Stem / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D020032:Tyrphostins / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D004791:Enzyme Inhibitors; D007093:Imidazoles; D015850:Interleukin-6; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D020032:Tyrphostins; D014662:Vasoconstrictor Agents; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D000804:Angiotensin II; C073402:PD 123319; C507927:Jak2 protein, rat; D053614:Janus Kinase 2