Division of Nephrology, Department of Medicine, Nephrology Research and Training Center, Center for Free Radical Biology, University of Alabama, Birmingham, AL, USA.
Blood. 2011 Jan 27;117(4):1301-7. doi: 10.1182/blood-2010-08-302505. Epub 2010 Nov 22.
One of the major attendant complications of multiple myeloma is renal injury, which contributes significantly to morbidity and mortality in this disease. Monoclonal immunoglobulin free light chains (FLCs) are usually directly involved, and tubulointerstitial renal injury and fibrosis are prominent histologic features observed in myeloma. The present study examined the role of monoclonal FLCs in altering the nuclear factor κ light chain enhancer of activated B cells (NF-κB) activity of renal epithelial cells. Human proximal tubule epithelial cells exposed to 3 different human monoclonal FLCs demonstrated Src kinase-dependent activation of the NF-κB pathway, which increased production of monocyte chemoattractant protein-1 (MCP-1). Tyrosine phosphorylation of inhibitor of κB kinases (IKKs) IKKα and IKKβ and a concomitant increase in inhibitor of κB (IκB) kinase activity in cell lysates were observed. Time-dependent, Src kinase-dependent increases in serine and tyrosine phosphorylation of IκBα and NF-κB activity were also demonstrated. Proteasome inhibition partially blocked FLC-induced MCP-1 production. These findings fit into a paradigm characterized by FLC-induced redox-signaling events that activated the canonical and atypical (IKK-independent) NF-κB pathways to promote a proinflammatory, profibrotic renal environment.
多发性骨髓瘤的主要伴随并发症之一是肾损伤，这对该病的发病率和死亡率有重大影响。单克隆免疫球蛋白游离轻链（FLC）通常直接参与其中，骨髓瘤中观察到的肾小管间质肾损伤和纤维化是突出的组织学特征。本研究探讨了单克隆 FLC 改变肾上皮细胞核因子 κ 轻链增强子活化 B 细胞（NF-κB）活性的作用。暴露于 3 种不同的人源性单克隆 FLC 的人近端肾小管上皮细胞表现出 Src 激酶依赖性 NF-κB 途径的激活，从而增加单核细胞趋化蛋白-1（MCP-1）的产生。在细胞裂解物中观察到 IκB 激酶（IKK）IKKα和 IKKβ的酪氨酸磷酸化以及 IκB 激酶活性的增加。还证明了 IκBα和 NF-κB 活性的 Src 激酶依赖性的时间依赖性丝氨酸和酪氨酸磷酸化增加。蛋白酶体抑制部分阻断了 FLC 诱导的 MCP-1 产生。这些发现符合这样一种模式，即 FLC 诱导的氧化还原信号事件激活了经典和非典型（不依赖于 IKK）NF-κB 途径，以促进促炎、促纤维化的肾环境。
