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

Abstract

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

Topical hypochlorite ameliorates NF-κB–mediated skin diseases in mice

“…IKKα regulates noncanonical NF-κB signaling by a group of TNF-like receptors, including lymphotoxin β receptor (LTβR) (19). LTβR activates NF-κB by proteasomal processing of the NF-κB precursor protein p100 into the mature p52 subunit, thereby stimulating expression of target genes including Ccl2 (20). As expected, in LTβR-exposed wild-type cells, we observed an accumulation of p52 protein and induced Ccl2 expression.…”

“…The method used was a repeated-measures ANOVA for ordinal data. We considered two factors: treatment (control vs. HOCI) and time (14,20, and 30 days) and an interaction term (treatment × time). The treatment factor allowed us to study differences between the control and HOCI groups, the time factor allowed us to study differences among the three time points, and the interaction term allowed us to determine whether differences between the control and HOCI groups were consistent over time.…”

The autophagic paradox in cancer therapy

“…It has been shown that NF-kB represses tumor necrosis factor-a-induced autophagy in Ewing sarcoma cells through activation of mTOR (Djavaheri-Mergny et al, 2006). The reason for these discrepancies remains unclear, but it is possible that the dimeric composition of NF-kB, as in other physiological contexts, may determine the functional outcome of NF-kB activation (Bren et al, 2001;Lovas et al, 2008).…”

A single NFκB system for both canonical and non-canonical signaling

“…Selective recruitment of RelB to the promoter region of these genes and in vitro binding assays between NFκB dimeric complexes and DNA probes suggested that RelB:p52 recognizes specific κB-binding sites that are different from those bound by RelA:p50 [89]. However, genome-wide gene expression analysis derived from LTβR-stimulated MEF revealed that the majority of the induced genes require both RelA-and RelB-containing dimers [90]. RelB:p52 and RelA:p50 complexes derived from eukaryotic cells showed similar ability to bind to consensus binding sites [91].…”