Hodgkin disease: pharmacologic intervention of the CD40-NFκB pathway by a protease inhibitor
| Autor: | Steven G. Irving, Yassamin J. Safiran, Jeffrey Cossman, Usha Kasid, Christina M. Annunziata |
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| Rok vydání: | 2000 |
| Předmět: | |
| Zdroj: | Blood. 96:2841-2848 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.v96.8.2841.h8002841_2841_2848 |
| Popis: | The malignant Reed-Sternberg cell of Hodgkin disease is an aberrant B cell that persists in an immunolgically mediated inflammatory infiltrate. Despite its nonproductive immunoglobulin genes, the Reed-Sternberg cell avoids the usual apoptotic fate of defective immune cells through an unknown mechanism. A likely candidate is the surface receptor, CD40, consistently expressed by Reed-Sternberg cells, and the first link in the pathway to NF-κB activation, the central regulator of cytokine production and apoptosis. CD40 signaling in B lymphocytes coordinates the immune response, including immunoglobulin isotype switch and Fas-mediated apoptosis. CD40-induced NF-κB activation is mediated by adapter proteins, the TNF receptor (TNFR)-associated factors (TRAFs), especially TRAFs 2, 3, and 5. Using a Hodgkin cell line, this study demonstrates that CD40 activation of NF-κB is mediated by proteolysis of TRAF3. Results further demonstrate that the pathway can be blocked by treatment with pharmacologic doses of a specific protease inhibitor, pepstatin-A, even in the presence of a mutated NF-κB inhibitor, I-κBα. The stability of TRAF3 regulates CD40/NF-κB–mediated control of the immune response, which is central to the biologic activity of the Reed-Sternberg cell. Prevention of TRAF3 proteolysis may be an entry point for design of novel pharmaceuticals to treat Hodgkin disease and immune system disorders. |
| Databáze: | OpenAIRE |
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