Accelerated apoptosis of lymphocytes by augmented induction of Bax in SSI-1 (STAT-induced STAT inhibitor-1) deficient mice

Abstract

Growth, differentiation, and programmed cell death (apoptosis) are mainly controlled by cytokines. The Janus kinase-signal transducers and activators of transcription (JAK-STAT) signal pathway is an important component of cytokine signaling. We have previously shown that STAT3 induces a molecule designated as SSI-1, which inhibits STAT3 functions. To clarify the physiological roles of SSI-1 in vivo, we generated, here, mice lacking SSI-1. These SSI-1؊͞؊ mice displayed growth retardation and died within 3 weeks after birth. Lymphocytes in the thymus and spleen of the SSI-1؊͞؊ mice exhibited accelerated apoptosis with aging, and their number was 20-25% of that in SSI-1؉͞؉ mice at 10 days of age. However, the differentiation of lymphocytes lacking SSI-1 appeared to be normal. Among various pro-and anti-apoptotic molecules examined, an up-regulation of Bax was found in lymphocytes of the spleen and thymus of SSI-1؊͞؊ mice. These findings suggest that SSI-1 prevents apoptosis by inhibiting the expression of Bax.The homeostatic regulation of cell populations is controlled by a balance among proliferation, growth arrest, and apoptosis, and this balance is mainly controlled by cytokines and growth factors. Cytokines act by binding to receptors expressed on the surfaces of responsive cells, which are associated with one or more members of the Janus kinase (JAK) family of cytoplasmic tyrosine kinases. The JAK-signal transducers and activators of transcription (STAT) signal pathway plays an important role in cytokine signaling (1-3), and is unique in that it features a direct linkage of receptor-ligand interaction on the cell surface to gene expression in the nucleus (4-6). However, the mechanism of negative control of cytokine actions involved in limiting their signal transductions is comparatively less well characterized. In 1997, the molecules that were expressed by stimulation of cytokine such as interleukin 6 (IL-6) and inhibited cytokine signal transmission by binding to JAK were isolated [STAT-induced STAT inhibitor-1 (SSI-1), suppressor of cytokine signaling (SOCS-1), Jak-binding protein (JAB)] (7-9). Subsequently, SSI-1 was found to form a family consisting of at least eight molecules, which were structurally characterized by an SH2 domain and a C-terminal conserved region (SC-motif͞SOCS-box͞CH-domain) (10-12), and it was recently known that SSI-1 inhibits not only IL-6 signaling but also interferon (IFN)-␥, IL-2, IL-3, and growth hormone signaling in vitro (13). It is expected that further study of SSI family molecules engaged in the negative feedback mechanism of cytokines will clarify the control mechanism of cytokines, which have remained obscure. MATERIALS AND METHODS Generation of SSI-1-Deficient Mice.A 129͞G mouse genomic library (Stratagene) containing the SSI-1 gene was screened, subcloned into the pBluescript vector, and characterized by restriction endonuclease mapping and DNA sequencing. A targeting vector was designed to replace the SSI-1 intron with phosphoglycerate kinase neo. This targeting...

Suppressor of Cytokine Signaling-1 Has IFN-γ-Independent Actions in T Cell Homeostasis

“…3D). This contrasts with results obtained from SOCS-1 Ϫ/Ϫ mice where increased apoptosis occurs, presumably due to the severe disease state of these mice (15).…”

“…Although studies in vitro suggest that SOCS-1 regulates signaling in response to a broad spectrum of cytokines, including IFN␣, IFN␤, IFN-␥, IL-2, IL-4, IL-6, IL-7, and TNF (5, 8 -13), analyses of SOCS-1-deficient mice have suggested a more specific role in vivo. SOCS-1-deficient mice die before weaning from a complex inflammatory disease characterized by fatty degeneration of the liver and macrophage infiltrates in the lung, pancreas, heart, and skin (14,15). We have established previously that IFN-␥ is a critical mediator of this disease, because mice that are deficient for both SOCS-1 and IFN-␥ survive to adulthood and appear in good health (16).…”

The biology of Stat4 and Stat6

“…This leads to a model where IL-4 signaling via Stat6 initially occurs unopposed but is subsequently dampened by a negative feedback mechanism through the IL-4/Stat6 dependent induction of SOCS1 expression. This is supported by the observation that Stat6 phosphorylation is prolonged in SOCS1-de®cient lymphocytes (Naka et al, 1998;Starr et al, 1998). SOCS proteins therefore may be important regulators for the termination of an immune or cytokine response.…”

Cytokine regulation of apoptosis and Bcl-2 expression in lymphocytes of patients with systemic lupus erythematosus

“…29 ± 33 Thus, defects of cell death signal transduction pathways in SLE might lead to the survival of autoreactive cells and to cell activation even without the expression of conventional activation markers. 34,35 Since the anti-apoptotic cytokines used here share a common receptor element, the gamma chain which uses denominated intracellular signaling molecules, 36 the study of cell death signal transduction and of Janus kinases or signal transducers (STATs) 37,38 and their inhibitors 39,40 is warranted in SLE.…”