Immunoglobulin light chains activate nuclear factor-κB in renal epithelial cells through a Src-dependent mechanism

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 kappa light chain enhancer of activated B cells (NF-kappa B) 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-kappa B pathway, which increased production of monocyte chemoattractant protein-1 (MCP-1). Tyrosine phosphorylation of inhibitor of kappa B kinases (IKKs) IKK alpha and IKK beta and a concomitant increase in inhibitor of kappa B (I kappa B) kinase activity in cell lysates were observed. Time-dependent, Src kinase-dependent increases in serine and tyrosine phosphorylation of I kappa B alpha and NF-kappa B 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-kappa B pathways to promote a proinflammatory, profibrotic renal environment.(Blood. 2011; 117(4): 1301-1307)