Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

KYM-1D4 cells are a subline derived from a human rhabdomyosarcoma which are highly sensitive to TNF-mediated cytotoxicity. They were selected for this study because they express human TNF-R and are therefore a more relevant target for comparing the potential therapeutic value of human TNF-inhibitory agents than the usual murine cell lines. Two recombinant soluble TNF-R-IgG fusion proteins, one containing p55 TNR-R, the other containing p75 TNF-R, and a recombinant monomeric soluble p55 TNF-R were all found to block the cytotoxicity generated by human TNF-alpha and LT as well as also murine TNF. The p55 TNF-R-IgG fusion protein (p55-sf2) was the most effective of the antagonists tested, requiring an equimolar, (based on a monomeric configuration of TNF-alpha) or a 3-fold higher (based on a trimeric configuration of TNF-alpha) molar concentration to inhibit the cytotoxicity mediated TNF-alpha by 50%. p55-sf2 was also as effective at inhibiting the cytotoxicity mediated by LT or murine TNF in the KYM-1D4 assay. In contrast, the monomeric soluble p55 TNF-R was the least effective inhibitor, requiring a > 4000-fold higher molar concentration than p55-sf2 to achieve a similar degree of protection. The fusion proteins, particularly p55-sf2, may be useful as human therapeutic agents, as at low concentrations they can prevent both TNF-alpha-mediated and LT-mediated effects on human cells. As TNF-R-IgG fusion proteins also block the action of murine TNF in vitro, they may also be useful in the investigation of murine models of human inflammatory disease.
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PMID:TNF receptor fusion proteins are effective inhibitors of TNF-mediated cytotoxicity on human KYM-1D4 rhabdomyosarcoma cells. 789 70

Using agonistic antibodies (Ab) we have examined whether the 75-kDa chain of the tumor necrosis factor receptor (p75 TNFR) is capable of mediating cytotoxic response and gene regulation alone or in cooperation with p55 TNFR. Addition of an anti-p75 TNFR polyclonal antiserum or anti-p75 monoclonal antibody (mAb) plus anti-immunoglobulin (Ig) led to cytotoxic response of human KYM-1 rhabdomyosarcoma cells. Anti-p75 mAb alone had no effect pointing out the importance of strong receptor stimulation for signal transduction into the cell. Simultaneous triggering of both the p55 and p75 TNFR by agonistic Ab resulted in additive cytotoxic action on KYM-1 cells. The anti-p75 mAb 3H5, directed to a non-TNF binding site on the human p75 TNFR, was used to confirm further the ability of the p75 TNFR to potentiate p55 TNFR-mediated cell death. While exhibiting no cytotoxicity by its own, 3H5 significantly augmented the cytotoxic effect of the anti-p55 mAb htr9 towards KYM-1 cells. Neither the anti-p75 TNFR antiserum nor anti-p75 mAb were cytotoxic for human U937 cells suggesting that the cytolysis resulting from p75 TNFR cross-linking is cell specific. Noteworthy, stimulation of the p75 TNFR with mAb plus anti-Ig or polyclonal antiserum led to a marked enhancement of the p55 TNFR-induced U937 cell death, indicating collaboration between the two TNFR in induction of cytotoxicity also in this cell line. However, 3H5 mAb did not affect the ability of anti-p55 mAb to lyse U937 cells. Altogether, these data demonstrate the difference between KYM-1 and U937 cell lines with respect to the role for the p75 TNFR in mediating cytotoxicity. Both TNFR were found to mediate cytomegalovirus (CMV) promoter activation in human SW480T-beta Gal cells and nuclear transcription factor kappa B (NF-kappa B) induction in this cell line as well as in KYM-1 cells. It was demonstrated for the first time that independent stimulation of both TNFR resulted in an additive effect on the CMV promoter activation and induction of the NF-kappa B. Taken together, these results indicate that the p75 TNFR induces cytotoxicity in a cell-specific manner and potentiates p55 TNFR-mediated cytotoxic response and gene regulation.
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PMID:Involvement of the tumor necrosis factor receptor p75 in mediating cytotoxicity and gene regulating activities. 795 75

The functional role of human tumor necrosis factor receptor (TNFR) p75 was studied by the use of TNFR p75-specific agonistic antibodies. Human SW480T adenocarcinoma cells, stably transfected with a reporter construct containing beta-galactosidase under the control of human cytomegalovirus immediate early enhancer, were stimulated with anti-TNFR p75 polyclonal antiserum or monoclonal antibodies followed by measurement of beta-galactosidase activity and analysis by electrophoretic mobility shift assays. It was found that cross-linking of TNFR p75 led to strong induction of the human cytomegalovirus enhancer as well as activation of nuclear factor-kappa B (NF-kappa B). Stimulation of TNFR p75 also mediated activation of NF-kappa B in human KYM-1 rhabdomyosarcoma cells but not in other cell types such as U937 and HL-60 monocytic cells or in Eahy 926 endothelial cells. NF-kappa B activation induced by TNFR p75 was delayed approximately 15 min compared with NF-kappa B activation induced by TNFR p55, indicating that the two TNFRs activate NF-kappa B through different signaling pathways. The data presented in this study identify intracellular responses mediated by TNFR p75 which have not been reported previously and suggest that TNFR p75-induced activation of NF-kappa B is strictly cell type-specific.
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PMID:Tumor necrosis factor receptor p75 mediates cell-specific activation of nuclear factor kappa B and induction of human cytomegalovirus enhancer. 812 5

In this study, we investigated the type of TNF receptor expressed by the human rhabdomyosarcoma cell line KYM-1 and related TNF-sensitive sublines and showed that the majority (> 90%) of TNF receptors were type II (p75) receptors with only a relatively small number (< 10%) of type I (p55) receptors. Selection with TNF alpha led to the isolation of KYM-1 related TNF-resistant cell lines of which three cloned lines showed a near to total loss of type II TNF receptors. To investigate further the role of each type of TNF receptor in the regulation of TNF-mediated cytotoxicity and the development of TNF resistance, we used receptor-specific antibodies and antisera, able to compete with ligand binding to the respective receptor molecules, but representing efficient agonists via crosslinking of receptors. We found that in KYM-1 and related TNF-sensitive sublines both type I and type II TNF receptors can be functional on their own, as selective cross-linking of each receptor subset lead to cytolysis. However, investigation of three TNF-resistant KYM-1 related cell lines by selective receptor stimulation via cross-linking indicated different mechanisms underlied the development of TNF-resistant for each receptor type. Our data indicate that resistance to TNF-mediated cytotoxicity in KYM-1 related cell lines can be developed both by a selective loss of type II receptor expression and the selective loss of type I receptor function without reduction in type I receptor numbers.
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PMID:Development of resistance to tumour necrosis factor (TNF alpha) in KYM-1 cells involves both TNF receptors. 818 67

We have previously hypothesized that the pro-inflammatory cytokine TNF alpha has a pivotal role in the pathogenesis of rheumatoid arthritis (RA). It mediates its effects by cross-linking surface p55 TNF receptors (TNF-R), which can be proteolytically cleaved to yield soluble fragments. Upon binding TNF alpha soluble TNF-R (sTNF-R) can inhibit its function. We investigated the enzymatic nature of the proteases involved in TNF-R cleavage, and found that this process is blocked by a synthetic inhibitor of matrix metallo-proteinase activity (MMP), BB-2275. Inhibition of TNF-R cleavage was observed in a number of different cell types, as detected by retention of surface bound TNF receptor and by less sTNF-R released into the cell supernatant. The augmentation of surface TNF-R expression was of biological relevance as TNF alpha-mediated necrosis of human KYM.1D4 rhabdosarcoma cells was enhanced approximately 15-fold in the presence of BB-2275. The addition of BB-2275 to rheumatoid synovial membrane cell cultures totally inhibited MMP activity and also significantly reduced the levels of soluble TNF alpha (P < 0.006), p55 sTNF-R (P < 0.006), and p75 sTNF-R (P < 0.004). Paradoxically, despite the reduction in soluble TNF alpha levels, the production of IL-1 beta, IL-6, and IL-8, cytokines whose production was previously demonstrated to be inhibited by the addition of neutralizing anti-TNF alpha antibody were not down-regulated by BB-2275. These results raise the interesting possibility that a close relationship exits between the enzyme(s) which process membrane-bound TNF alpha, and those involved in surface TNF-R cleavage. Furthermore our observations suggest that hydroxamate inhibitors of MMP activity which block TNF alpha secretion and TNF-R cleavage may not modulate down-stream effects of TNA alpha, and as such suggest that the precise specificity of these compounds will be highly relevant to their clinical efficacy in inflammatory diseases.
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PMID:Paradoxical effects of a synthetic metalloproteinase inhibitor that blocks both p55 and p75 TNF receptor shedding and TNF alpha processing in RA synovial membrane cell cultures. 867 95