title: Immunoglobulin light chains activate nuclear factor-κB in renal epithelial cells through a Src-dependent mechanism.
abstract: 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.
authors.affiliation: Division of Nephrology, Department of Medicine, Nephrology Research and Training Center, Center for Free Radical Biology, University of Alabama, Birmingham, AL, USA.
authors.forename: Wei-Zhong
authors.initials: WZ
authors.lastname: Ying
authors.forename: Pei-Xuan
authors.initials: PX
authors.lastname: Wang
authors.forename: Kristal J
authors.initials: KJ
authors.lastname: Aaron
authors.forename: Kolitha
authors.initials: K
authors.lastname: Basnayake
authors.forename: Paul W
authors.initials: PW
authors.lastname: Sanders
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007147:Immunoglobulin Light Chains / Q000494:pharmacology* / Q000502:physiology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D018932:Chemokine CCL2; D007147:Immunoglobulin Light Chains; D016328:NF-kappa B; D011719:Pyrazines; D014443:Tyrosine; D000069286:Bortezomib; D019061:src-Family Kinases; D051550:I-kappa B Kinase