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Am J Physiol Cell Physiol 293: C1843-C1850, 2007. First published October 3, 2007; doi:10.1152/ajpcell.00370.2007 Free Article
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GROWTH, DIFFERENTIATION, AND APOPTOSIS

Opposing roles of EGF in IFN-{alpha}-induced epithelial barrier destabilization and tissue repair

Judith Lechner,1 Nadia A. Malloth,1 Paul Jennings,1 Daniel Heckl,2 Walter Pfaller,1 and Thomas Seppi2

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

Submitted 17 August 2007 ; accepted in final form 2 October 2007

Balance between damaging influences and repair mechanisms determines the degree of tissue deterioration by inflammatory and other injury processes. Destabilization of the proximal tubular barrier has been previously shown to be induced by IFN-{alpha}, a cytokine crucial for linking innate and adaptive immune responses. EGF was implicated in rescue mechanisms from renal injury. To study the interplay between the two processes, we determined if EGF can prevent IFN-{alpha}-induced barrier permeabilization. EGF did not counteract but even exacerbated the IFN-{alpha}-induced decrease of transepithelial electrical resistance in LLC-PK1 monolayers. For this effect Erk1/2 activation was necessary, linking barrier regulation to EGF-induced cell cycle progression. In contrast to its damage-intensifying effect, EGF also facilitated the regeneration of epithelial barrier function after the termination of IFN-{alpha} treatment. This effect was not mediated by Erk1/2 activation or cell proliferation since U0126, an Erk1/2 inhibitor, did not prevent but ameliorated recovery. However, EGF accelerated the downregulation of caspase-3 in recovering cells. Similarly, a pan-caspase inhibitor was able to block caspase activity and, concomitantly, promote restoration of barrier function. Thus, barrier repair might be linked to an EGF-mediated antiapoptotic mechanism. EGF appears to sensitize epithelial cells to the detrimental effects of IFN-{alpha} but also helps to restore barrier function in the healing phase. The observed dual effect of EGF might be explained by the different impact of proproliferative and antiapoptotic signaling pathways during and after cytokine treatment. The timing of epithelial exposure to damaging agents and repair factors was identified as a crucial parameter determining tissue fate.

cytokine; proximal tubular cells; proliferation; type I interferon; apoptosis


Address for reprint requests and other correspondence: J. Lechner, Div. of Physiology, Dept. of Physiology and Medical Physics, Innsbruck Medical Univ., Fritz-Pregl-Strasse 3, Innsbruck A-6020, Austria (e-mail: Judith.Lechner{at}i-med.ac.at)






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