Hodgkin disease: pharmacologic intervention of the CD40-NF kappa B pathway by a protease inhibitor.
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-kappa B 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-kappa B 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-kappa B 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-kappa B inhibitor, I-kappa B alpha. The stability of TRAF3 regulates CD40/NF-kappa B-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. (Blood. 2000;96:2841-2848)
Annunziata
C M
CM
Georgetown University Medical Center, Washington, DC 20007, USA.
Safiran
Y J
YJ
Irving
S G
SG
Kasid
U N
UN
Cossman
J
J
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D016282:Aspartic Acid Endopeptidases / Q000502:physiology*; D019013:CD40 Antigens / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis; D015195:Drug Design; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009363:Neoplasm Proteins / Q000502:physiology*; D010436:Pepstatins / Q000494:pharmacology* / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D016539:Reed-Sternberg Cells / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D015398:Signal Transduction / Q000187:drug effects*; D048008:TNF Receptor-Associated Factor 3; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D019014:fas Receptor / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D019013:CD40 Antigens; D016207:Cytokines; D015850:Interleukin-6; D016328:NF-kappa B; D009363:Neoplasm Proteins; D010436:Pepstatins; D011480:Protease Inhibitors; D011506:Proteins; C484406:TANK protein, human; D048008:TNF Receptor-Associated Factor 3; D019014:fas Receptor; C014195:Streptomyces pepsin inhibitor; D016282:Aspartic Acid Endopeptidases; C031375:pepstatin