Cm. Annunziata et al., Hodgkin disease: pharmacologic intervention of the CD40-NF kappa B pathwayby a protease inhibitor, BLOOD, 96(8), 2000, pp. 2741-2748
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.