Induction of JAB/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 is involved in gp130 resistance in cardiovascular system in rat treated with cardiotrophin-1 in vivo.
CIS (cytokine-inducible SH2 protein), SOCS (suppressor of cytokine signaling), or SSI (signal transducers and activators of transcription [STAT]-induced STAT inhibitor) proteins are a family of cytokine-inducible negative regulators of cytokine signaling via Janus kinase (JAK)-STAT pathways. Given the evidence that the JAK-STAT pathway plays a critical role in the cardiovascular system, the primary objective of this study was to assess the effects of the CIS family on JAK-STAT signaling in the cardiovascular system in rats treated with cardiotrophin-1 (CT-1), an interleukin-6 family of cytokines. Intravenous injection of 20 microgram/kg body weight of CT-1 induced a transient, marked increase in STAT3 activation in various tissues, including heart and lung, and subsequent upregulation of 2 members of the CIS family, JAK-binding protein (JAB)/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3, in the same tissues. It was also observed that CIS3 was directly associated with JAK2 in vivo. Pretreatment with the same dose of CT-1 60 minutes before significantly attenuated the STAT3 activation induced by a second injection of CT-1. We previously reported that intravenous injection of CT-1 results in the nitric oxide (NO)-dependent hypotension accompanied by the induction of inducible NO synthase mRNA. In rats pretreated with CT-1, the induction of inducible NO synthase mRNA or hypotension by subsequent CT-1 injection was not observed. Forced expression of JAB or CIS3, but not other CISs, directly blocked CT-1-induced STAT3 activation in 293 cells. These results suggest that JAB and CIS3 serve as endogenous inhibitors of CT-1-mediated JAK-STAT signaling in the cardiovascular system in vivo.
Hamanaka
I
I
Department of Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Saito
Y
Y
Yasukawa
H
H
Kishimoto
I
I
Kuwahara
K
K
Miyamoto
Y
Y
Harada
M
M
Ogawa
E
E
Kajiyama
N
N
Takahashi
N
N
Izumi
T
T
Kawakami
R
R
Masuda
I
I
Yoshimura
A
A
Nakao
K
K
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D015152:Blotting, Northern; D015153:Blotting, Western; D002319:Cardiovascular System / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000008:administration & dosage / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007022:Hypotension / Q000139:chemically induced; D007275:Injections, Intravenous; D053614:Janus Kinase 2; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism* / Q000494:pharmacology; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000302:isolation & purification / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism; D014157:Transcription Factors; D015854:Up-Regulation / Q000187:drug effects
D015703:Antigens, CD; D002352:Carrier Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; C494201:Il6st protein, rat; D008562:Membrane Glycoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C491589:Socs1 protein, rat; C491410:Socs3 protein, rat; C494088:Stat3 protein, rat; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D050822:Cytokine Receptor gp130; C092073:cardiotrophin 1; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2