A Critical Role for the RelA Subunit of Nuclear Factor κB in Regulation of Multiple Immune-response Genes and in Fas-induced Cell Death

Abstract

Binding sites for the nuclear factor (NF)-κB transcription factor have been identified within control regions of many genes involved in inflammatory and immune responses. Such κB sites are often found adjacent to those of interferon (IFN)-γ–inducible transcription factors, suggesting a requirement for multiple signaling pathways for gene regulation. Using fibroblasts from RelA (p65)-deficient mice generated by gene targeting, we have investigated the role of this subunit of NF-κB in gene activation by microbial lipopolysaccharide, tumor necrosis factor α, and in possible synergism with the IFN-γ–signaling pathway. Our results indicate not only that RelA is required for activation of key genes involved in adaptive (acquired) immune responses, including major histocompatibility complex class I, CD40, and the Fas death receptor, but also that both NF-κB–inducing signals and IFN-γ are necessary for maximal activation. In contrast, neutrophil-specific chemokine genes KC and MIP-2, which can function as nonspecific mediators in innate immune responses, were strongly induced by RelA in the absence of IFN-γ. Our results show that RelA plays a critical role in activation of immune system genes in response to nonspecific stimuli and demonstrate a novel proapoptotic function for this protein in Fas-induced cell death.

Mycobacterium tuberculosisAntigens Induce the Differentiation of Dendritic Cells from Bone Marrow

“…Toward identifying intracellular intermediates that may be modulated during MTSA-mediated DC differentiation, we looked at the activation of NF-B that has been suggested to play a vital role in the differentiation of DCs (43)(44)(45)(46)(47). Indeed, the p65 subunit of NF-B did translocate to the nucleus within 30 min of stimulation, indicating a possible role of this transcription factor during MTSAinduced differentiation process.…”

“…In addition, it has recently been reported that differentiation of DCs from monocytes by calcium ionophores or LPS involves the activation of NF-B (46). To test whether MTSA-induced differentiation of DCs involved the activation of NF-B, we stimulated BM cells with either MTSA or GM-CSF for varying periods of time and looked at the nuclear translocation of the p65 subunit of NF-B, which is the predominant species translocated to the nucleus upon activation and has been shown to regulate multiple immune response genes (47). It is clear from Fig.…”

NF-κB-dependent cytokine secretion controls Fas expression on chemotherapy-induced premature senescent tumor cells

“…In addition, a crucial role for NF-kB in induction of Fas expression has been demonstrated (Ouaaz et al, 1999;Ku¨hnel et al, 2000). To identify which components of secretory phenotype are modulated by NF-kB in premature senescent tumor cells, we knocked-down expression of RelA, the main member of the NF-kB family, in MCF-7 and A549 cells by using lentiviruses encoding small hairpin RNA.…”

An Essential Role of the NF-κB/Toll-Like Receptor Pathway in Induction of Inflammatory and Tissue-Repair Gene Expression by Necrotic Cells

“…Our recent studies have demonstrated a critical role for NF-B in regulation of KC and MIP-2 (29). Thus, one intriguing possibility was that induction of KC expression by necrotic cells was mediated by activation of NF-B in viable cells, after interaction with necrotic cells.…”

“…Western blotting for I B␣ was carried out with cytosolic extracts from ϳ10 5 MEFs by using a rabbit polyclonal IgG against the carboxyl terminus of I B␣ (Santa Cruz Biotechnology, Santa Cruz, CA). Northern blotting was carried out as described previously (29) with probes made from cDNA fragments amplified by RT-PCR with gene-specific primers.…”