| Autor: |
Riches, David W.H., Chan, Edward D., Zahradka, Elizabeth A., Winston, Brent W., Remigio, Linda K., Lake, Fiona R. |
| Zdroj: |
Journal of Biological Chemistry; August 1998, Vol. 273 Issue: 35 p22800-22806, 7p |
| Abstrakt: |
Tumor necrosis factor-α (TNFα) is recognized by the cell-surface receptors CD120a (p55) and CD120b (p75). In the present study, we have investigated the role of these receptors in the expression of NO2−, a stable metabolite of nitric oxide, and inducible nitric oxide synthase (iNOS) by mouse macrophages. Specific antibody-mediated aggregation of CD120a (p55) induced NO2−accumulation in culture supernatants and iNOS mRNA expression in macrophage lysates, whereas cross-linking of CD120b (p75) had a minimal effect. In contrast, simultaneous cross-linking of both receptors led to a marked augmentation in NO2−and iNOS mRNA expression. Antibody-mediated blockade of CD120a (p55) completely inhibited NO2−expression in response to TNFα, whereas blockade of CD120b (p75) reduced NO2−accumulation by ∼50%. Specific ligation of CD120a (p55) with either (i) human TNFα or (ii) by incubation with mouse TNFα following pretreatment of macrophages with blocking concentrations of anti-CD120b (p75) antibody resulted in a similar reduction in NO2−production in response to TNFα. Quantification of iNOS mRNA, protein, and NO2−expression during independent and co-ligation of CD120a (p55) and CD120b (p75) indicated that iNOS mRNA and protein expression was transient in nature when CD120a (p55) was cross-linked alone but was prolonged when both receptors were simultaneously cross-linked. In addition, cross-linking both receptors also led to a potentiation of NO2−accumulation in culture supernatants that was more pronounced at later time points. These findings suggest that while cross-linking of CD120a (p55) is necessary and sufficient for iNOS mRNA and NO2−expression, CD120b (p75) participates by (i) increasing the sensitivity of the cells to TNFα, probably by “passing” ligand to CD120a (p55), and (ii) initiating a signaling event that results in a more sustained induction of iNOS mRNA and protein and thereby augments the production of nitric oxide. |
| Databáze: |
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