Tumor necrosis factor-stimulated gene

Bik release also occurs when Ial heavy chains are covalently transferred to hyaluronan in the extracellular matrix [23], This is a major component of cumulus cell-oocyte during fertilization and fibroblasts and mesothelial cells during inflammation. The heavy chains coupled to hyaluronan molecules bind to the cell surface through association with the hyaluronan receptor (CD44). The tumor necrosis factor-stimulated gene 6 (TSG-6) enhances the association of hyaluronan-linked heavy chains with CD44 and increases the release of free Bik [24, 25]. 

Janssen U, Thomas G, Giant T, Phillips A. Expression of inter-alpha-trypsin inhibitor and tumor necrosis factor-stimulated gene 6 in renal proximal tubular epithelial cells. Kidney... 

Bennett, B.L., Cruz, R., Lacson, R.G. and Manning, A.M. (1997) Interleukin-4 suppression of tumor necrosis factor alpha-stimulated E-selectin gene transcription is mediated by STAT6 antagonism of NF-kappaB. Journal of Biological Chemistry 272, 10212-10219. 

Hofbauer LC, Lacey DL, Dunstan CR, Spelsberg TC, Riggs BL, Khosla S (1999) Interleukin-lbeta and tumor necrosis factor-alpha, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone 25 255-259... 

Alvaro-Gracia, J. M., Zvaifler, N. J., Brown, C. B., Kaushansky, K., Firestein, G. S. (1991). Cytokines in chronic inflammatory arthritis VI. Analysis of the synovial cells involved in granulocyte-macrophage colony-stimulating factor production and gene expression in rheumatoid arthritis and its regulation by IL-1 and tumor necrosis factor-a J. Immunol 146,3365-71. 

Corticosteroids suppress both humoral and cellular immunity. Single doses produce a redistribution of lymphocytes with a concentration dependent decrease of CD4 and CDS positive cells. This in vivo lymphopenic effect correlates with the in vitro inhibition of stimulated T-cell proliferation. Furthermore, corticosteroids are able to inhibit the expression of genes coding for IL-1, IL-2, IL-6, interferon a, and tumor necrosis factor, TNE-a. Chronic administration decreases the size and also the cellu-larity of lymphoid tissues like lymph nodes, spleen, and thymus. Corticosteroids have more effect on the primary immune response and are less effective against previously sensitized immune responses. Their suppressive effects are more pronounced for T-cell immune responses than for the humoral immune response. 

Anti-arthritic effect. Oral administration of AJA, a cannabinoid acid devoid of psychoactivity, reduced joint tissue damage in rats with adjuvant arthritis. Peripheral blood monocytes (PBM) and synovial fluid monocytes (SFM) were isolated from healthy subjects and patients with inflammatory arthritis, respectively, treated with AJA (0-30 mM) in vitro, and then stimulated with lipopolysaccharide. Cells were harvested for messenger RNA (mRNA), and supernatants were collected for cytokine assay. Addition of AJA to PBM and SFM in vitro reduced both steady-state levels of interleukin-ly (IL-ly) mRNA and secretion of IL-ly in a concentration-dependent manner. Suppression was maximal (50.4%) at 10 mM AJA (p < 0.05 vs untreated controls, n = 7). AJA did not influence tumor necrosis factor-a (TNF-a) gene expression in or secretion from PBM . 

The presence of tumor necrosis factor a directly leads to apoptosis via interaction with the tumor necrosis factor receptor, one of a class of receptors referred to as death receptors. NF-kB, which must enter the nucleus to initiate apoptosis, is a transcription factor sequestered in the cytoplasm by inhibitor of kB (IkB). The binding of TNFa to its receptor leads to the ubiquitin-dependent proteolysis of IkB, allowing NF-kB to enter the nucleus. The activation of apoptosis results directly from the stimulation of NF-kB, a transcription factor whose phosphorylation is controlled by vanadium compounds. In a global gene expression study, it was found that diabetes increased the formation of IkB, whereas vanadium compound treatment lowered the production of this inhibitor [101]. The activation of the TNFR also activates the caspase proteins, a class of proteases that cleave proteins after specific aspartate residues. 

Szalkowski, D., White-Carrington, S., Berger, J., and Zhang, B. (1995). Antidiabetic Thiazolidinediones Block the Inhibitory Effect of Tumor Necrosis Factor-a on Differentiation, Insulin-Stimulated Glucose Uptake, and Gene Expression in 3T3-L1 Cells. Endocrinology 136, 1474—1481. 

Several cytokine genes have been found to reduce tumors by stimulating localized inflammatory and/or immune responses. These include interleukin-1 (IL-1), IL-2, IL-4, IL-6, IL-7, IL-12, interferon gamma (IFN-y), tumor necrosis factor-a (TNF-a), and granulocyte-macrophage colony-stimulating factor (GM-CSF). 

Zoja C, Wang JM, Bettoni S, Sironi M, Renzi D, Chiaffarino F, Abboud HE, Van Damme J, Mantovani A, Remuzzi G, Rambaldi A. Interleukin-1 b and tumor necrosis factor-a induce gene expression and production of leukocyte chemotactic factors, colony-stimulating factors, and interleukin-6 in human mesangial cells. Am J Pathol 1991 138 991-1003. 

Fig. 15.11 Si gnaling by the tumor necrosis factor (TNF) receptor. Binding of TNF to its receptor induces association and activation for further signaling of several proteins which activate distinct signaling pathways. Assembly of the multiprotein complex on the cytoplasmic side is mediated mainly via death domains (DD) ofthe receptor and the adaptor protein TRADD. FADD induces apoptosis via activation of initiator caspase 8. TRAF2 and RIP mediate activation of transcription via two main ways. One way uses phosphorylation ofthe inhibitor IkB by IkB kinase (IKK) to induce its ubiquitin-mediated proteolytic destruction and the relieve ofNF cB inhibition. Another way leads to activation ofthe JNK pathway (see Chapter 10) and stimulation of transcription of diverse target genes.

Tumor necrosis factor a (TNF-a) is a pro-inflammatory cytokine which augments its own production and the synthesis of other inflammatory mediators. It stimulates the pyrogen, IL-1(3 and regulates genes coding for other inflammatory mediators such as IL-1, IL-... 

Lapinet, J. A., Scapini, P., Calzetti, F., Perez, O., and Cassatella, M. A. (2000). Gene expression and production of tumor necrosis factor alpha, interleukin-1 beta (IL-lbeta), IL-8, macrophage inflammatory protein lalpha (MIP-lalpha), MIP-lbeta, and gamma interferon-inducible protein 10 by human neutrophils stimulated with group B meningococcal outer membrane vesicles. Infect. Immun. 68, 6917-6923. 

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