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Cytokine Signal (cytokine + signal)

Distribution by Scientific Domains

Medical Sciences	100%

Selected Abstracts

Association study of polymorphisms in SOCS family genes with type 1 diabetes mellitus

INTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 1 2006
R. Ni
Summary Suppressors of cytokine signalling (SOCS) proteins play important roles in the negative regulation of cytokine signal. We first searched for polymorphisms in SOCS-1, SOCS-3 and SOCS-5 genes, and examined the association of the polymorphisms with type 1 diabetes (T1D). As a result, we did not find any significant associations between SOCS genes and T1D. [source]

Ras and Signal Transducer and Activator of Transcription (STAT) Are Essential and Sufficient Downstream Components of Janus Kinases in Cell Proliferation

CANCER SCIENCE, Issue 5 2000
Rumiko Mizuguchi
Cytokines exert their activities in cell growth and differentiation by binding specific cell membrane receptors. Janus kinases (JAKs) are cytoplasmic protein tyrosine kinases that physically interact with intracellular domains of the cytokine receptors and they play crucial roles in transducing signals triggered by the cytokine-receptor interaction. We have previously shown that conditional activation of JAK through membrane-proximal dimerization confers cytokine-independence on interleukin-3 (IL-3)-dependent Ba/F3 lymphoid cells and that the cytokine-independent proliferation is completely inhibited by dominant negative Ras. In this work, we demonstrate that ectopic expression of a dominant negative form of Stat5, a major signal transducer and activator of transcription (STAT) expressed in Ba/F3 cells, also inhibits JAK-triggered mitogenesis. In contrast, overexpression of constitutively active Ras or conditional activation of Stat5 by chemical dimerization fails to confer cytokine-independence. However, concomitant activation of ectopic Ras and Stat5 molecules in Ba/F3 cells suffices for cell proliferation in the absence of IL-3. Our results indicate that Ras and STAT are essential and sufficient components of JAK-triggered mitogenesis. Our findings further indicate that the cytokine signal bifurcates into Ras and STAT pathways following JAK activation. [source]

Instructive cytokine signals in dendritic cell lineage commitment

IMMUNOLOGICAL REVIEWS, Issue 1 2010
Michael A. Schmid
Summary:, Clarifying the signals that lead to dendritic cell (DC) development and identifying cellular intermediates on their way to DC differentiation are essential steps to understand the dynamic regulation of number, localization, and functionality of these cells. In the past decade, much knowledge on cytokines, transcription factors, and successive progenitors involved in steady-state and demand-adapted DC development was gained. From the stage of multipotent progenitors, DCs are generated from Flt3+ intermediates, irrespective of lymphoid or myeloid commitment, making fms-related tyrosine kinase 3 ligand one of the major regulators for DC development. Additional key cytokines involved are granulocyte,macrophage colony-stimulating factor (GM-CSF) and M-CSF, with each being essential for particular DC subsets and leading to specific activation of downstream transcription factors. In this review, we seek to draw an integrative view on how instructive cytokine signals acting on intermediate progenitors might lead to the generation of specific DC subsets in steady-state and during inflammation. We hypothesize that the lineage potential of a progenitor might be determined by the set of cytokine receptors expressed that make it responsive to further receive lineage instructive signals. Commitment to a certain lineage might consequently occur when lineage-relevant cytokine receptors are further upregulated and others for alternative lineages are lost. Along this line, we emphasize the role that diverse microenvironments have in influencing the generation of DC subsets with specific functions throughout the body. [source]

Signal transduction of inflammatory cytokines and tumor development

CANCER SCIENCE, Issue 6 2006
Akihiko Yoshimura
It has been estimated that >20% of all malignancies are initiated or exacerbated by inflammation. Until recently, the molecular basis of this process has not been clarified. However, recent studies have uncovered the molecular mechanism of intracellular signaling pathways of inflammatory cytokines such as tumor necrosis factor (TNF)-,, interferon (IFN)-, and interleukin (IL)-6. Three major transcription factors including NF-,B, STAT1 and STAT3 have been shown to play major roles in transmitting inflammatory cytokine signals to the nucleus. One function of NF-,B and STAT3 in tumor cells is the promotion of cell growth and cell survival through the induction of target genes, whose products promote cell division and inhibit apoptosis. In addition, NF-,B and STAT1 are important transcription factors that induce inflammatory mediators from inflammatory cells, especially macrophages, while STAT3 often antagonizes this process. STAT1 is generally believed to be an anti-oncogene because it promotes apoptosis through p53, but it could promote inflammation-mediated tumor development by enhancing tissue injury, remodeling, fibrosis and inflammation. Hence, the inhibition of NF-,B and STATs offers a strategy for treatment of a variety of malignancies and can convert inflammation-induced tumor growth into inflammation-induced tumor regression. (Cancer Sci 2006; 97) [source]

Selective functional inhibition of JAK-3 is sufficient for efficacy in collagen-induced arthritis in mice

ARTHRITIS & RHEUMATISM, Issue 8 2010
Tsung H. Lin
Objective All ,-chain cytokines signal through JAK-3 and JAK-1 acting in tandem. We undertook this study to determine whether the JAK-3 selective inhibitor WYE-151650 would be sufficient to disrupt cytokine signaling and to ameliorate autoimmune disease pathology without inhibiting other pathways mediated by JAK-1, JAK-2, and Tyk-2. Methods JAK-3 kinase selective compounds were characterized by kinase assay and JAK-3,dependent (interleukin-2 [IL-2]) and ,independent (IL-6, granulocyte,macrophage colony-stimulating factor [GM-CSF]) cell-based assays measuring proliferation or STAT phosphorylation. In vivo, off-target signaling was measured by IL-22, and erythropoietin (EPO),mediated models, while on-target signaling was measured by IL-2,mediated signaling. Efficacy of JAK-3 inhibitors was determined using delayed-type hypersensitivity (DTH) and collagen-induced arthritis (CIA) models in mice. Results In vitro, WYE-151650 potently suppressed IL-2,induced STAT-5 phosphorylation and cell proliferation, while exhibiting 10,29-fold less activity against JAK-3,independent IL-6, or GM-CSF,induced STAT phosphorylation. Ex vivo, WYE-151650 suppressed IL-2,induced STAT phosphorylation, but not IL-6,induced STAT phosphorylation, as measured in whole blood. In vivo, WYE-151650 inhibited JAK-3,mediated IL-2,induced interferon-, production and decreased the natural killer cell population in mice, while not affecting IL-22,induced serum amyloid A production or EPO-induced reticulocytosis. WYE-151650 was efficacious in mouse DTH and CIA models. Conclusion In vitro, ex vivo, and in vivo assays demonstrate that WYE-151650 is efficacious in mouse CIA despite JAK-3 selectivity. These data question the need to broadly inhibit JAK-1,, JAK-2,, or Tyk-2,dependent cytokine pathways for efficacy. [source]