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)

The interleukin-6 (IL-6) cytokine family plays an important role in regulating cellular responses during hematopoiesis. We report here that mice homozygous for a knock-in mutation in the IL-6 cytokine family receptor signaling subunit glycoprotein (gp) 130 (gp130(Y757F/Y757F)) that leads to gp130-dependent signal transducers and activators of transcription (STAT) 1/3 hyperactivation develop a broad spectrum of hematopoietic abnormalities, including splenomegaly, lymphadenopathy, and thrombocytosis. To determine whether STAT3 hyperactivation was responsible for the perturbed hematopoiesis in gp130(Y757F/Y757F) mice, we generated gp130(Y757F/Y757F) mice on a Stat3 heterozygous (Stat3(+/-)) background to specifically reduce gp130-dependent activation of STAT3, but not STAT1. Normal hematopoiesis was observed in gp130(Y757F/Y757F):Stat3(+/-) bone marrow and spleen, with no evidence of the splenomegaly and thrombocytosis displayed by gp130(Y757F/Y757F) mice. The perturbed cellular composition of thymus and lymph nodes in gp130(Y757F/Y757F) mice was also alleviated in gp130(Y757F/Y757F): Stat3(+/-) mice. Furthermore, we show that hematopoietic cells from gp130(Y757F/Y757F) mice exhibited increased survival and proliferation in response to IL-6 family cytokines. Collectively, these data provide genetic evidence that gp130-dependent STAT3 hyperactivation during hematopoiesis has pathological consequences affecting multiple organs, and therefore identify the threshold of STAT3 signaling elicited by IL-6 family cytokines as a critical determinant for hematopoietic homeostasis.
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PMID:The threshold of gp130-dependent STAT3 signaling is critical for normal regulation of hematopoiesis. 1565 55

The increased incidence of systemic lupus erythematosus (SLE) in recent decades might be related to changes in modern dietary habits. Since sodium chloride (NaCl) promotes pathogenic T cell responses, we hypothesize that excessive salt intake contributes to the increased incidence of autoimmune diseases, including SLE. Given the importance of dendritic cells (DCs) in the pathogenesis of SLE, we explored the influence of an excessive sodium chloride diet on DCs in a murine SLE model. We used an induced lupus model in which bone marrow-derived dendritic cells (BMDCs) were incubated with activated lymphocyte-derived DNA (ALD-DNA) and transferred into C57BL/6 recipient mice. We observed that a high-salt diet (HSD) markedly exacerbated lupus progression, which was accompanied by increased DC activation. NaCl treatment also stimulated the maturation, activation and antigen-presenting ability of DCs in vitro. Pretreatment of BMDCs with NaCl also exacerbated BMDC-ALD-DNA-induced lupus. These mice had increased production of autoantibodies and proinflammatory cytokines, more pronounced splenomegaly and lymphadenopathy, and enhanced pathological renal lesions. The p38 MAPK-STAT1 pathway played an important role in NaCl-induced DC immune activities. Taken together, our results demonstrate that HSD intake promotes immune activation of DCs through the p38 MAPK-STAT1 signaling pathway and exacerbates the features of SLE. Thus, changes in diet may provide a novel strategy for the prevention or amelioration of lupus or other autoimmune diseases.
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PMID:High salt diet accelerates the progression of murine lupus through dendritic cells via the p38 MAPK and STAT1 signaling pathways. 3229 43