Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / metabolism*
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Blood Pressure / drug effects
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Blotting, Northern
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Blotting, Western
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Cardiovascular System / drug effects
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Cardiovascular System / metabolism*
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Carrier Proteins / metabolism*
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Carrier Proteins / pharmacology
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Cell Line
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Cytokine Receptor gp130
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Cytokines / administration & dosage
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Cytokines / metabolism*
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / metabolism
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Dose-Response Relationship, Drug
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Drug Administration Schedule
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Hypotension / chemically induced
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Injections, Intravenous
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Janus Kinase 2
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Male
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Membrane Glycoproteins / metabolism*
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase / metabolism
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Nitric Oxide Synthase Type II
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Protein-Tyrosine Kinases / metabolism
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Proteins / metabolism*
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Proteins / pharmacology
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Proto-Oncogene Proteins*
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RNA, Messenger / isolation & purification
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RNA, Messenger / metabolism
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Rats
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Rats, Wistar
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Repressor Proteins*
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STAT3 Transcription Factor
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / metabolism
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Transcription Factors*
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Up-Regulation / drug effects
Substances
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Antigens, CD
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Carrier Proteins
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Cytokines
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DNA-Binding Proteins
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Il6st protein, rat
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Membrane Glycoproteins
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Proteins
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Proto-Oncogene Proteins
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RNA, Messenger
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Repressor Proteins
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STAT3 Transcription Factor
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Socs1 protein, rat
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Socs3 protein, rat
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Stat3 protein, rat
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators
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Transcription Factors
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Cytokine Receptor gp130
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cardiotrophin 1
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, rat
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Protein-Tyrosine Kinases
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Jak2 protein, rat
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Janus Kinase 2