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Am J Physiol Cell Physiol 294: C153-C160, 2008. First published November 21, 2007; doi:10.1152/ajpcell.00120.2007
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GROWTH, DIFFERENTIATION, AND APOPTOSIS

IFN- induces barrier destabilization and apoptosis in renal proximal tubular epithelium

¹Division of Physiology, Department of Physiology and Medical Physics, and ²Department of Therapeutic Radiology and Oncology, Innsbruck Medical University, Innsbruck, Austria

Submitted 27 March 2007 ; accepted in final form 14 November 2007

Type I IFNs, like IFN-, are major immune response regulators produced and released by activated macrophages, dendritic cells, and virus-infected cells. Due to their immunomodulatory functions and their ability to induce cell death in tumors and virus-infected cells, they are used therapeutically against cancers, viral infections, and autoimmune diseases. However, little is known about the adverse effects of type I IFNs on nondiseased tissue. This study examined the effects of IFN- on cell death pathways in renal proximal tubular cells. IFN- induced apoptosis in LLC-PK1 cells, characterized by the activation of caspase-3, -8, and -9, DNA fragmentation, and nuclear condensation. IFN- also caused mitochondrial depolarization. Effector caspase activation was dependent on caspase-8 and -9. In addition to apoptosis, IFN- exposure also decreased renal epithelial barrier function, which preceded apoptotic cell death. Caspase inhibition did not influence permeability regulation while significantly attenuating and delaying cell death. These results indicate that IFN- causes programmed cell death in nondiseased renal epithelial cells. IFN--induced apoptosis is directed by an extrinsic death receptor signaling pathway, amplified by an intrinsic mitochondrial pathway. Caspase-dependent and -independent apoptotic mechanisms are involved. These findings reveal a novel aspect of IFN- actions with implications for normal renal function in immune reactions and during IFN- therapy.

cytokines; interferon; cell death; transepithelial electrical resistance; caspase

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