Autocrine/Paracrine secretion of IL-6 family cytokines causes angiotensin II-induced delayed STAT3 activation.
We recently reported that angiotensin II (AngII) biphasically activates the JAK/STAT pathway and induces delayed phosphorylation of STAT3 in the late stage (120 min) in cardiomyocytes. This study was designed to determine the mechanism of delayed phosphorylation of STAT3. Conditioned medium prepared from AngII-stimulated cardiomyocytes could reproduce the tyrosine phosphorylation of STAT3 at 5 min. This delayed phosphorylation was almost completely inhibited by anti-gp130 blocking antibody RX435, but not by TAK044 (ET-A/B-R antagonist), prazosin, or propranolol. AngII induced phosphorylation of gp130 in the late stage, which was temporally in parallel with the delayed phosphorylation of STAT3. AngII augmented IL-6, CT-1, and LIF mRNA expression at 30-60 min, but not CNTF expression. AngII increased IL-6 protein levels by 3-fold in the conditioned media at 2 h compared with the control. These findings indicated that AngII-induced delayed activation of STAT3 is caused by autocrine/paracrine secreted IL-6 family cytokines.
Sano
M
M
Cardiopulmonary Division, Department of Internal Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
Fukuda
K
K
Kodama
H
H
Takahashi
T
T
Kato
T
T
Hakuno
D
D
Sato
T
T
Manabe
T
T
Tahara
S
S
Ogawa
S
S
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000235:genetics; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006131:Growth Inhibitors / Q000235:genetics; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles; D015850:Interleukin-6 / Q000235:genetics* / Q000502:physiology*; D007700:Kinetics; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D009206:Myocardium / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*
D020934:Ciliary Neurotrophic Factor; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D015534:Trans-Activators; D000804:Angiotensin II