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 signalin g), or SSI (signal transducers and activators of transcription [STAT]-induc ed STAT inhibitor) proteins are a family of cytokine-inducible negative reg ulators of cytokine signaling via Janus kinase (JAK)-STAT pathways. Given t he evidence that the JAK-STAT pathway plays a critical role in the cardiova scular system, the primary objective of this study was to assess the effect s of the CIS family on JAK-STAT signaling in the cardiovascular system in r ats treated with cardiotrophin-1 (CT-1), an interleukin-6 family of cytokin es, Intravenous injection of 20 mug/kg body weight of CT-1 induced a transi ent, marked increase in STAT3 activation in various tissues, including hear t 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 tiss ues. It was also observed that CIS3 was directly associated with JAK2 in vi vo. Pretreatment with the same dose of CT-1 60 minutes before significantly attenuated the STAT3 activation induced by a second injection of CT-I, We previously reported that intravenous injection of CT-1 results in the nitri c oxide (NO)-dependent hypotension accompanied by the induction of inducibl e NO synthase mRNA. In rats pretreated with CT-1, the induction of inducibl e NO synthase mRNA or hypotension by subsequent CT-I injection was not obse rved. Forced expression of JAB or CIS3, but not other CISs, directly blocke d CT-1-induced STAT3 activation in 293 cells. These results suggest that JA B and CIS3 serve as endogenous inhibitors of CT-1-mediated JAK-STAT signali ng in the cardiovascular system in vivo.