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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Migration of leukocytes across an endothelium-epithelium bilayer as a model of renal interstitial inflammation

¹Clinical Division of General Internal Medicine, Clinical Department of Internal Medicine and ²Division of Physiology, Department of Physiology and Medical Physics, Innsbruck Medical University, Innsbruck, Austria

Submitted 4 August 2006 ; accepted in final form 2 April 2007

Interstitial inflammation has emerged as a key event in the development of acute renal failure. To gain better insight into the nature of these inflammatory processes, the interplay between tubular epithelial cells, endothelial cells, and neutrophils (PMN) was investigated. A coculture transmigration model was developed, composed of human dermal microvascular endothelial (HDMEC) and human renal proximal tubular cells (HK-2) cultured on opposite sides of Transwell growth supports. Correct formation of an endoepithelial bilayer was verified by light and electron microscopy. The model was used to study the effects of endotoxin (LPS), tumor necrosis factor (TNF)-, and -melanocyte-stimulating hormone (-MSH) by measuring PMN migration and cytokine release. To distinguish between individual roles of microvascular endothelial and epithelial cells in transmigration processes, migration of PMN was investigated separately in HK-2 and HDMEC monolayers. Sequential migration of PMN through endothelium and epithelium could be observed and was significantly increased after proinflammatory stimulation with either TNF- or LPS (3.5 ± 0.58 and 2.76 ± 0.64-fold vs. control, respectively). Coincubation with -MSH inhibited the transmigration of PMN through the bilayer after proinflammatory stimulation with LPS but not after TNF-. The bilayers produced significant amounts of IL-8 and IL-6 mostly released from the epithelial cells. Furthermore, -MSH decreased LPS-induced IL-6 secretion by 30% but had no significant effect on IL-8 secretion. We established a transmigration model showing sequential migration of PMN across microvascular endothelial and renal tubular epithelial cells stimulated by TNF- and LPS. Anti-inflammatory effects of -MSH in this bilayer model are demonstrated by inhibition on PMN transmigration and IL-6 secretion.

coculture; polymorphonuclear neutrophil migration; HK-2; interleukin-8; interleukin-6; -melanocyte-stimulating hormone

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