Differential RelA- and RelB-dependent gene transcription in LTβR-stimulated mouse embryonic fibroblasts

Background: Lymphotoxin signaling via the lymphotoxin-beta receptor (LT beta R) 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 LT beta R crosslinking is NF-kappa B. Two signaling pathways have been described, the classical inhibitor of NF-kappa B alpha (I kappa B alpha)-regulated and the alternative p100-regulated pathway that result in the activation of p50-RelA and p52-RelB NF-kappa B heterodimers, respectively. Results: Using microarray analysis, we investigated the transcriptional response downstream of the LT beta R in mouse embryonic fibroblasts (MEFs) and its regulation by the RelA and RelB subunits of NF-kappa B. We describe novel LT beta R-responsive genes that were regulated by RelA and/or RelB. The majority of LT beta R-regulated genes required the presence of both RelA and RelB, revealing significant crosstalk between the two NF-kappa B activation pathways. Gene Ontology ( GO) analysis confirmed that LT beta R-NF-kappa B 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 LT beta R signaling. Moreover, LT beta R activation inhibited expression of a key adipogenic transcription factor, peroxisome proliferator activated receptor-gamma (pparg), suggesting that LT beta R signaling may interfere with adipogenic differentiation. Conclusion: Microarray analysis of LT beta R-stimulated fibroblasts provided comprehensive insight into the transcriptional response of LT beta R signaling and its regulation by the NF-kappa B family members RelA and RelB.