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Tumor Necrosis Factor Superfamily (tumor + necrosis_factor_superfamily)
Selected AbstractsCharacterization of a transneuronal cytokine family Cbln , regulation of secretion by heteromeric assemblyEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2007Takatoshi Iijima Abstract Cbln1, a member of the C1q and tumor necrosis factor superfamily, plays crucial roles as a cerebellar granule cell-derived transneuronal regulator of synapse integrity and plasticity in Purkinje cells. Although other Cbln family members, Cbln2,Cbln4, have distinct spatial and temporal patterns of expression throughout the CNS, their biochemical and biological properties have remained largely uncharacterized. Here, we demonstrated that in mammalian heterologous cells, Cbln2 and Cbln4 were secreted as N-linked glycoproteins, like Cbln1. In contrast, despite the presence of a functional signal sequence, Cbln3 was not secreted when expressed alone but was retained in the endoplasmic reticulum (ER) or cis -Golgi because of its N-terminal domain. All members of the Cbln family formed not only homomeric but also heteromeric complexes with each other in vitro. Accordingly, when Cbln1 and Cbln3 were co-expressed in heterologous cells, a proportion of the Cbln1 proteins was retained in the ER or cis -Golgi; conversely, some Cbln3 proteins were secreted together with Cbln1. Similarly, in wild-type granule cells expressing Cbln1 and Cbln3, Cbln3 proteins were partially secreted and reached postsynaptic sites on Purkinje cell dendrites, while Cbln3 was almost completely degraded in cbln1 -null granule cells. These results indicate that like Cbln1, Cbln2 and Cbln4 may also serve as transneuronal regulators of synaptic functions in various brain regions. Furthermore, heteromer formation between Cbln1 and Cbln3 in cerebellar granule cells may modulate each other's trafficking and signaling pathways; similarly, heteromerization of other Cbln family proteins may also have biological significance in other neurons. [source] The Roles of Osteoprotegerin and Osteoprotegerin Ligand in the Paracrine Regulation of Bone ResorptionJOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2000Lorenz C. Hofbauer Abstract Although multiple hormones and cytokines regulate various aspects of osteoclast formation, the final two effectors are osteoprotegerin ligand (OPG-L)/osteoclast differentiation factor (ODF), a recently cloned member of the tumor necrosis factor superfamily, and macrophage colony,stimulating factor. OPG-L/ODF is produced by osteoblast lineage cells and exerts its biological effects through binding to its receptor, osteoclast differentiation and activation receptor (ODAR)/receptor activator of NF-,B (RANK), on osteoclast lineage cells, in either a soluble or a membrane-bound form, the latter of which requires cell-to-cell contact. Binding results in rapid differentiation of osteoclast precursors in bone marrow to mature osteoclasts and, at higher concentrations, in increased functional activity and reduced apoptosis of mature osteoclasts. The biological activity of OPG-L/ODF is neutralized by binding to osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF), a member of the TNF-receptor superfamily that also is secreted by osteoblast lineage cells. The biological importance of this system is underscored by the induction in mice of severe osteoporosis by targeted ablation of OPG/OCIF and by the induction of osteopetrosis by targeted ablation of OPG-L/ODF or overexpression of OPG/OCIF. Thus, osteoclast formation may be determined principally by the relative ratio of OPG-L/ODF to OPG/OCIF in the bone marrow microenvironment, and alterations in this ratio may be a major cause of bone loss in many metabolic disorders, including estrogen deficiency and glucocorticoid excess. That changes in but two downstream cytokines mediate the effects of large numbers of upstream hormones and cytokines suggests a regulatory mechanism for osteoclastogenesis of great efficiency and elegance. [source] Stimulation of glucocorticoid-induced tumor necrosis factor receptor family-related protein ligand (GITRL) induces inflammatory activation of microglia in cultureJOURNAL OF NEUROSCIENCE RESEARCH, Issue 10 2010Heehong Hwang Abstract Glucocorticoid-induced tumor necrosis factor receptor family-related protein ligand (GITRL) is a member of the tumor necrosis factor superfamily (TNFSF) and is known to act as a costimulator in the immune system by binding to GITR. GITRL is expressed in endothelial cells, dendritic cells, macrophages, and B cells, but it is not known whether GITRL is expressed in brain microglia cells. Here, we investigated the expression of GITR and GITRL and their potential role in microglia cells. Using BV-2 mouse microglia cells and mouse primary microglia cultures, we have demonstrated that 1) both GITR and GITRL are expressed in microglia cells; 2) stimulation of GITRL induces inflammatory activation of microglia on the basis of production of nitric oxide (NO) and expression of inducible nitric oxide synthase, cyclooxygenase-2, CD40, and matrix metalloproteinase-9; 3) GITRL-mediated microglial NO production partially depends on p38 MAPK, JNK, and nuclear factor-,B pathways; and 4) GITRL stimulation also induces microglia cell death. These results indicate that GITR and GITRL are functionally expressed on brain microglia and that the stimulation of GITRL can induce inflammatory activation of microglia. The GITR/GITRL system may play an important role in neuroinflammation. © 2010 Wiley-Liss, Inc. [source] Light up-regulated on B lymphocytes and monocytes in rheumatoid arthritis mediates cellular adhesion and metalloproteinase production by synoviocytesARTHRITIS & RHEUMATISM, Issue 4 2007Young Mo Kang Objective To study the expression of LIGHT (tumor necrosis factor superfamily 14) and herpesvirus entry mediator (HVEM; tumor necrosis factor receptor superfamily 14) in rheumatoid arthritis (RA) and to determine the regulatory role of LIGHT on the effector functions of fibroblast-like synoviocytes (FLS). Methods The expression of LIGHT and HVEM was assessed by immunohistochemical staining of synovial tissue and by flow cytometric analysis of mononuclear cells. The presence of HVEM and lymphotoxin , receptor was measured by reverse transcriptase,polymerase chain reaction and by flow cytometry. The regulation of effector molecules, including matrix metalloproteinases (MMPs) and adhesion molecules, was evaluated. The adhesiveness of FLS was determined by adhesion assay. Results HVEM was detected in most cell types within rheumatoid synovial tissue, while only a few cells were positive for LIGHT. In RA patients, LIGHT expression was significantly up-regulated only in CD20+ B cells and monocytes, whereas the mean fluorescence intensity of HVEM was down-regulated in mononuclear cells. The stimulation of FLS with LIGHT resulted in the production of MMPs and the expression of adhesion molecules, which were efficiently inhibited by dexamethasone. LIGHT-mediated up-regulation of MMPs and intercellular adhesion molecule 1 was blocked by inhibitors of NF-,B and JNK, whereas up-regulation of vascular cell adhesion molecule 1 was blocked by inhibitors of phosphatidylinositol 3-kinase, as well as NF-,B. Conclusion These data suggest that binding of LIGHT with its receptors may play a role in the progression of inflammation within rheumatoid synovium, especially by mediating the interactions between infiltrating inflammatory cells and stromal cells. These findings thus emphasize the relevance of LIGHT as a potential therapeutic target in RA. [source] | |||||||||||||