NFκB mediates apoptosis through transcriptional activation of Fas (CD95) in adenoviral hepatitis

Abstract

Listen

Translate article

NFKB MEDIATES APOPTOSIS THROUGH TRANSCRIPTIONAL ACTIVATION OF FAS (CD95) IN ADENOVIRAL HEPATITIS L. Zender, E Ktihnel, Y. Paul, C. Trautwein, S. Kubicka, M.P. Manns Dept. of Gastroenterology and Hepatology, Medical School Hannover. NFKB is an essential survival factor under several physiological conditions such as embryonal liver development and liver regener£tion. However,_ NFw.B is also a main mediator of the cellular response to a variety ot extracelhilar stress stimuli and it has been shown that some viral induced host cell apopt~is appears to be dependent on NFKB activation. We have assessed the role of ~ellular stress r e~mmse during adenoviral hepatitis in a nude mouse model using adenoviral vectors expressing I.aeZ as a control and a mutant fo,-m of Ird~xto inhibit NFr, B activity. Tail vene administration of a ~ r e s s i n g adenoviral vector induces a strong expression and DNA binding activity of p53 and NFr~B in the mouse liver as demonstrated I~ western blot and gel shift ananysis. P53 activation eccurrs at later tune points, whereas NFKB DNA binding activity correlates with the up-regulation of Fas (CD95) mRNA in Northern Blot experiments during the early phaso of adenoviral hepatitis. However, FasL (CI~5L) mRNA was not ri~,ulated in the course of aaonoviral hepatitis. The rapid inctmse ofNFr.B DNA binding after adenoviral infection of the liver could be inhibited very_ efficiently by bcBa as shown by gel shift experiments. Compared to [he LacZ--con_trol virus the [KE~tz-expressing adenoviral vector also significantly inhibits the inoreaso of Fas (CD95) mRNA expression in particular in the very early phase of the hepatitis. Reporter gone expert" -ents in hepatoma cell lines with a Fas-promoterluc3i~f~e ~°n t~-~ t i%°~s~y ~t~iiatt~=l~e ~e%°~i~Fa~e~Cev~n~Sc~ ) m f ~ A e ~ F r , B-dap~dont inoreaso of F ~ " ( ~ ) 5 ) transcription was assessed in vivo by easp~_ 3 assays and TUNEL tests. Compared to the control, Ir.Ba-adenoviral infection results in reduced ~ 3 activity during the early phaso of viral he~.titis and in a prevention of live~ cell apoptosis 24h atteiadonoviral admmistration. Inteiestingly, NFrJB mediatixi liver cell apoptosis upon viral infection was evident even in a phase when TNF(x was already induced as shown by the time course of TNFct serum levels. Our results implicate that in contrast to chemotherapy p53 does not activate Fas (CD95) in adenoviral induced hepatitis. Howeve~ Fas (CD95) is transcriptionally qp-reg#ated by NFkB wliich in turn determines liver cell apoptusis 24h after hifection.Therefore our study demonstrates for the first tune a new proapoptotic function of NF~B in Fas (CD95) mediated apoptusis of hepatocytes. The proor anti-apoptotic role of NFr,~B appears to 5e more det~'mined by the nature of the death stimulus than by the origin of the tissue. [ C03/03 ]