Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the importance of suppressor of cytokine signaling-3 (SOCS3) in the regulation of hematopoietic growth factor signaling generally, and of G-CSF-induced cellular responses specifically, we created mice in which the Socs3 gene was deleted in all hematopoietic cells. Although normal until young adulthood, these mice then developed neutrophilia and a spectrum of inflammatory pathologies. When stimulated with G-CSF in vitro, SOCS3-deficient cells of the neutrophilic granulocyte lineage exhibited prolonged STAT3 activation and enhanced cellular responses to G-CSF, including an increase in cloning frequency, survival, and proliferative capacity. Consistent with the in vitro findings, mutant mice injected with G-CSF displayed enhanced neutrophilia, progenitor cell mobilization, and splenomegaly, but unexpectedly also developed inflammatory neutrophil infiltration into multiple tissues and consequent hind-leg paresis. We conclude that SOCS3 is a key negative regulator of G-CSF signaling in myeloid cells and that this is of particular significance during G-CSF-driven emergency granulopoiesis.
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PMID:SOCS3 is a critical physiological negative regulator of G-CSF signaling and emergency granulopoiesis. 1497 38

The balance between pro- and anti-inflammatory cytokines modulates inflammation. Intracellular inhibitors of signaling, in turn, contribute to the negative regulation of cytokines. One of these inhibitors is suppressor of cytokine signaling-1 (SOCS-1). Socs1(-/-) mice die by 3 weeks of age with inflammation and fatty necrosis of the liver. Here, cre/loxP deletion of Socs1 was used to investigate the contribution of specific cells/tissues to inflammatory disease. Mice with SOCS-1 deficiency in myeloid and lymphoid cells, but not lymphoid alone, became ill at 50 to 250 days of age. These mice developed splenomegaly and T-cell/macrophage infiltration of many organs, including liver, lung, pancreas, and muscle. There were also abnormally high levels of the proinflammatory cytokines interferon gamma (IFN-gamma), tumor necrosis factor (TNF), and interleukin-12 (IL-12), and activated T cells circulating in these mice. Socs1(null) T cells were found to be hypersensitive to multiple cytokines, including IL-1, IL-2, and IL-12, resulting in IFN-gamma production without requiring T-cell receptor (TCR) ligation. Additionally, Socs1(null) macrophages produced excessive amounts of IL-12 and TNF in response to other cytokines, including IFN-gamma. A dysregulated cytokine network between T cells and macrophages is thus associated with this inflammatory disease. These findings indicate that SOCS-1 is critical in both T cells and macrophages for preventing uncontrolled inflammation.
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PMID:Suppressor of cytokine signaling-1 in T cells and macrophages is critical for preventing lethal inflammation. 1589 15