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

I. Hamanaka, Y. Saito, H. Yasukawa, I. Kishimoto, K. Kuwahara, Y. Miyamoto, M. Harada, E. Ogawa, N. Kajiyama, N. Takahashi, T. Izumi, R. Kawakami, I. Masuda, A. Yoshimura, K. Nakao

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

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 μg/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, bur 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.

Original languageEnglish
Pages (from-to)727-732
Number of pages6
JournalCirculation research
Volume88
Issue number7
DOIs
Publication statusPublished - 2001 Apr 13
Externally publishedYes

Keywords

  • CIS family
  • Cardiotrophin-1
  • JAB/SOCS-1/SSI-1
  • JAK-STAT signaling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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