Hodgkin disease: pharmacologic intervention of the CD40-NF kappa B pathwayby a protease inhibitor

The malignant Reed-Sternberg cell of Hodgkin disease is an aberrant B cell that persists in an immunolgically mediated inflammatory infiltrate. Despit e its nonproductive immunoglobulin genes, the Reed-Sternberg cell avoids th e usual apoptotic fate of defective immune cells through an unknown mechani sm. A likely candidate is the surface receptor, CD40, consistently expresse d by Reed-Sternberg cells, and the first link in the pathway to NF-kappa B activation, the central regulator of cytokine production and apoptosis. CD4 0 signaling in B lymphocytes coordinates the immune response, including imm unoglobulin isotype switch and Fas-mediated apoptosis, CD40-induced NF-kapp a B activation is mediated by adapter proteins, the TNF receptor (TNFR)-ass ociated factors (TRAFs), especially TRAFs 2, 3, and 5, Using a Hodgkin cell line, this study demonstrates that CD40 activation of NF-kappa B is mediat ed by proteolysis of TRAF3, Results further demonstrate that the pathway ca n be blocked by treatment with pharmacologic doses of a specific protease i nhibitor, pepstatin-A, even in the presence of a mutated NF-kappa B inhibit or, I-kappa B alpha, The stability of TRAF3 regulates CD40/NF-kappa B-media ted control of the immune response, which is central to the biologic activi ty of the Reed-Sternberg cell. Prevention of TRAF3 proteolysis may be an en try point for design of novel pharmaceuticals to treat Hodgkin disease and immune system disorders. (Blood, 2000;96:2841-2848) (C) 2000 by The America n Society of Hematology.