Hodgkin disease: pharmacologic intervention of the CD40-NFκB 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-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.

霍奇金病的恶性里德 - 施特恩伯格细胞是一种异常的B细胞，它存在于免疫介导的炎症浸润中。尽管其免疫球蛋白基因无功能，但里德 - 施特恩伯格细胞通过一种未知机制避免了缺陷免疫细胞通常的凋亡命运。一个可能的因素是里德 - 施特恩伯格细胞持续表达的表面受体CD40，它是激活核因子 - κB（NF - κB）途径中的第一个环节，而NF - κB是细胞因子产生和凋亡的核心调节因子。B淋巴细胞中的CD40信号传导协调免疫反应，包括免疫球蛋白同种型转换和Fas介导的凋亡。CD40诱导的NF - κB激活是由衔接蛋白、肿瘤坏死因子受体（TNFR）相关因子（TRAFs）介导的，特别是TRAF2、3和5。本研究利用一种霍奇金细胞系表明，NF - κB的CD40激活是由TRAF3的蛋白水解作用介导的。结果进一步表明，即使在存在突变的NF - κB抑制剂I - κBα的情况下，用特定蛋白酶抑制剂胃蛋白酶抑素 - A进行药物剂量的治疗也可阻断该途径。TRAF3的稳定性调节CD40 / NF - κB介导的免疫反应控制，这对里德 - 施特恩伯格细胞的生物学活性至关重要。防止TRAF3蛋白水解可能是设计治疗霍奇金病和免疫系统疾病的新型药物的一个切入点。