Differential RelA- and RelB-dependent gene transcription in LTbetaR-stimulated mouse embryonic fibroblasts.
BACKGROUND
Lymphotoxin signaling via the lymphotoxin-beta receptor (LTbetaR) has been implicated in biological processes ranging from development of secondary lymphoid organs, maintenance of spleen architecture, host defense against pathogens, autoimmunity, and lipid homeostasis. The major transcription factor that is activated by LTbetaR crosslinking is NF-kappaB. Two signaling pathways have been described, the classical inhibitor of NF-kappaB alpha (IkappaBalpha)-regulated and the alternative p100-regulated pathway that result in the activation of p50-RelA and p52-RelB NF-kappaB heterodimers, respectively.


RESULTS
Using microarray analysis, we investigated the transcriptional response downstream of the LTbetaR in mouse embryonic fibroblasts (MEFs) and its regulation by the RelA and RelB subunits of NF-kappaB. We describe novel LTbetaR-responsive genes that were regulated by RelA and/or RelB. The majority of LTbetaR-regulated genes required the presence of both RelA and RelB, revealing significant crosstalk between the two NF-kappaB activation pathways. Gene Ontology (GO) analysis confirmed that LTbetaR-NF-kappaB target genes are predominantly involved in the regulation of immune responses. However, other biological processes, such as apoptosis/cell death, cell cycle, angiogenesis, and taxis were also regulated by LTbetaR signaling. Moreover, LTbetaR activation inhibited expression of a key adipogenic transcription factor, peroxisome proliferator activated receptor-gamma (pparg), suggesting that LTbetaR signaling may interfere with adipogenic differentiation.


CONCLUSIONS
Microarray analysis of LTbetaR-stimulated fibroblasts provided comprehensive insight into the transcriptional response of LTbetaR signaling and its regulation by the NF-kappaB family members RelA and RelB.
Lovas
Agnes
A
Research Group Immunology, Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany. lovas@fli-leibniz.de
Radke
Dörte
D
Albrecht
Daniela
D
Yilmaz
Z Buket
ZB
Möller
Ulrich
U
Habenicht
Andreas J R
AJ
Weih
Falk
F
D016475:3T3 Cells; D000818:Animals; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053259:Lymphotoxin beta Receptor / Q000378:metabolism*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D051996:Transcription Factor RelA / Q000235:genetics*; D051841:Transcription Factor RelB / Q000235:genetics*; D014158:Transcription, Genetic
C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; C498144:Rela protein, mouse; C497594:Relb protein, mouse; D051996:Transcription Factor RelA; D051841:Transcription Factor RelB