IL-1β Promotes a New Function of DNase I as a Transcription Factor for the Fas Receptor Gene

Dhivya Thiyagarajan, Hege L. Pedersen, Natalya Seredkina, Kjersti D. Horvei, Lorena Arranz, Ramon Sonneveld, Tom Nijenhuis, Johan van der Vlag, Ole P. Rekvig

Recently we described that endonuclease inactive DNase I translocated into the nucleus in response to increased endogenous IL-1β expression. Here, we demonstrate impact and function of translocated DNase I in tubular cells. Effect of cytokines on expression level and nuclear localisation of DNase I and corresponding levels of Fas receptor (FasR) and IL-1β were determined by confocal microscopy, qPCR and western blot analyses, in presence or absence of siRNA against IL-1β and DNase I mRNA. Nuclear DNase I bound to theFASpromotor region as determined by chromatin immuno-precipitation analysis. Data demonstrate that; (i) translocation of DNase I depended on endogenousde novo-expressed IL-1β, (ii) nuclear DNase I boundFASDNA, (iii) FasR expression increased after translocation of DNase I, (iv) interaction ofexogenousFas ligand (FasL) with upregulated FasR induced apoptosis in human tubular cells stimulated with TNFα. Thus, translocated DNase I most probably binds the promoter region of theFASgene and function as a transcription factor for FasR. In conclusion, DNase I not only executes chromatin degradationduringapoptosis and necrosis, but also primes the cellsforapoptosis by enhancing FasR expression.