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

Abstract

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 g/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. he Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is activated in a rapid, transient manner and has been shown to be critical in many biological responses to cytokines. 1,2 Recently, a family of proteins that functions in a negative feedback loop to regulate signaling by cytokine receptors via JAK-STAT pathway has been identified by several groups and is referred to as the CIS (cytokine-inducible SH2-containing protein), 3 SOCS (suppressor of cytokine signaling), 4 or SSI (STAT-induced STAT inhibitor) 5 family. Presently, the CIS/SOCS/SSI family consists of at least 7 members of proteins and shares 2 homologous domains, an SH2 domain and a C-terminal-conserved domain called CIS homology domain. 6,7 Most CISs seem to be induced by several cytokines, and at least 3 CIS family members, CIS, JAB/SOCS-1/SSI-1, and CIS3/SOCS-3/ SSI-3, are proved to block JAK-STAT signaling by binding cytokine receptors or JAKs. 6 JAB and CIS3 directly bind to the kinase domain of JAKs and thereby inhibit interferon (IFN)-mediated STAT1 signaling and leukemia inhibitory factor (LIF)-mediated or interleukin (IL)-6 -mediated STAT3 activation in mouse myeloid leukemia M1 cells. 8 CIS3 is also found to bind to gp130 and regulate the signaling. 9 -11 Thus, evidence was accumulated that JAB or CIS3 exerts negative regulators of JAK-STAT signaling in hematopoietic and immune systems. 8,12 However, the significance of the negative regulatory mechanism of JAK-STAT pathway in cardiovascular system is little understood.Cardiotrophin-1 (CT-1), a member of the IL-6 superfamily, is substantially expresse...

Suppressor of Cytokine Signaling-3 Is Recruited to the Activated Granulocyte-Colony Stimulating Factor Receptor and Modulates its Signal Transduction

“…Treatment with human rG-CSF resulted in a dramatic increase of SOCS-3 mRNA within 45 min. This rapid induction of SOCS-3 was similar to that observed with other cytokines (47)(48)(49) and this indicates that SOCS-3 is an immediate early gene induced by G-CSF to rapidly modulate G-CSFR-mediated signaling. The strong and rapid induction of SOCS-3 mRNA in myeloid cells by G-CSF reported in this study, together with the previously reported potent induction of SOCS-3 by G-CSF, GM-CSF, and IL-3 in bone marrow cells (22), is a strong indication for SOCS-3 being an important regulator of signal transduction in immune cells.…”

Suppressor of cytokine signaling-3 is a biomechanical stress–inducible gene that suppresses gp130-mediated cardiac myocyte hypertrophy and survival pathways

“…On the other hand, activation of AKT was observed predominantly at the late phase and continued for 14 days following TAC. SOCS3 mRNA and protein is induced in the heart by in vivo infusion of gp130 cytokines (23). In addition, recent studies have revealed that the SOCS3 promoter contains a functionally important STAT-binding element (21).…”

“…Functionally, CIS and SOCS1-3 proteins interact with cytokine receptors and/or JAKs, thereby inhibiting activation of kinases and STATs. SOCS3 is induced by a variety of cytokines, including CT-1 and LIF (21)(22)(23). SOCS3 binds to JAKs via cytokine receptor, thereby inhibiting the cytokine receptor signaling (24,25).…”

Cardiotrophin-1 Review

“…The interaction between STAT3 and ERK1/2 in CT-1-induced signaling contributes to development of cardiac hypertrophy 31,87,89 . New fi ndings also indicate that the major pathway responsible for the hypertrophic responses to CT-1 is not JAK-STAT3 pathway nor MEK1-ERK1/2 pathway, but MEK5-ERK5 pathway 49,90 . In vivo, the death of ventricular myocytes leads to heart failure, and downregulation of survival signals and/or augmentation of pro-apoptotic signals are likely to be important components of disease processes.…”