NF-kappa B, which consists of two polypeptides, p50 (M(r) 50K) and p65/RelA (M(r) 65K), is thought to be a key regulator of genes involved in responses to infection, inflammation and stress. Indeed, although developmentally normal, mice deficient in p50 display functional defects in immune responses. Here we describe the generation of mice deficient in the RelA subunit of NF-kappa B. Disruption of the relA locus leads to embryonic lethality at 15-16 days of gestation, concomitant with a massive degeneration of the liver by programmed cell death or apoptosis. Embryonic fibroblasts from RelA-deficient mice are defective in the tumour necrosis factor (TNF)-mediated induction of messenger RNAs for I kappa B alpha and granulocyte/macrophage colony stimulating factor (GM-CSF), although basal levels of these transcripts are unaltered. These results indicate that RelA controls inducible, but not basal, transcription in NF-kappa B-regulated pathways.
"Our study also reveals a critical role of RelA in protecting keratinocytes from inflammation-induced apoptosis. This is in accordance with described functions of NF-B in the protection from cell death (Beg et al., 1995b; Seitz et al., 2000). NF-B regulates expression of anti-apoptotic genes such as cellular inhibitors of apoptosis (cIAPs) and X-linked inhibitors of apoptosis (XIAPs) (Barkett and Gilmore, 1999). "
[Show abstract][Hide abstract] ABSTRACT: Strong inhibition of NF-κB signaling in the epidermis results in spontaneous skin inflammation in mice and men. Since there is evidence for linkage between polymorphisms within the NF-κB signaling pathway and human inflammatory skin phenotypes, we asked whether partial functional inhibition of NF-κB signaling in epidermal keratinocytes can modulate clinically relevant skin inflammation. We therefore mutated rela specifically in the epidermis of mice (RelAE-MUT mice). These mice show no inflammatory phenotype. Induction of contact allergy, but not croton oil- induced irritant dermatitis, resulted in stronger ear swelling and increased epidermal thickness in RelAE-MUT mice. Both contact allergen and croton oil treatment led to increase expression of calgranulins A and B (S100A8/ A9) in RelAE-MUT mice. Epidermal hyperproliferation in RelAE-MUT mice was non-cell autonomous since cultured primary epidermal keratinocytes from RelAE-MUT mice showed reduced proliferation compared to controls. These results demonstrate that epidermal RelA specifically regulates DTH-induced skin inflammation. In addition, we here describe an essential but non- specific function of RelA in the protection of epidermal keratinocytes from apoptosis. Our study identifies functions of NF-κB signaling in the epidermis and corroborates a specific role of epidermal keratinocytes in the regulation of skin inflammation
Journal of Investigative Dermatology 04/2014; DOI:10.1038/jid.2014.193 · 7.22 Impact Factor
"Immunohistochemistry of LPS-treated liver remnants showed the remarkable decrease of nuclear reactivity and sparse reactivity of cytoplasm with the antibody to activated p65 at 8 or 10 h compared with controls or GL-treated remnants (Fig. S4). Although the activation of NF-κB is associated with potent inflammatory responses in hepatic injury, key roles for this factor in inhibition of apoptosis in the liver have been also demonstrated definitively experimentally , . In conclusion, in mouse liver injury induced by a single injection of LPS/GalN, HMGB1 protein appears to be implicated in the (direct and/or indirect) inhibition of a signal pathway associated with anti-apoptosis, i.e. down-regulation of GSTO1, and to stimulate apoptosis of hepatocytes rather than to act as pro-inflammatory factors in this experimental model. "
[Show abstract][Hide abstract] ABSTRACT: HMGB1 is a nuclear component involved in nucleosome stabilization and transcription regulation, but extracellularly it is able to serve as a potential late mediator of lethality. In the present study, we explored inflammation-promoting activity of HMGB1 and blockade of extracellular release of HMGB1 by glycyrrhizin (GL) in LPS/GalN-triggered mouse liver injury. At 1 to 10 h after LPS/GalN-treatment, mice were anesthetized to collect blood from heart puncture, and serum transaminase and HMGB1 were evaluated. Administration of LPS/GalN precipitated tissue injury associated with time-dependent alteration in HMGB1 serum levels. At 8 h nuclear immunoreactive products were remarkably reduced and extracellular HMGB1 expression was found exclusively in the pericentral foci. The treatment with GL significantly down-regulated the serum levels of ALT, AST, and HMGB1 in addition to the strong inhibition of tissue injury and extracellular immunoreactivity to HMGB1 and to acetylated-lysine. Furthermore, GL brought about a significant decrease in the number of apoptotic hepatocytes labeled with TUNEL-method. On the basis of these results, three apoptosis-associated genes were identified with microarray analysis and real-time PCR. The ChIP-assay revealed the binding of HMGB1 protein to Gsto1 promoter sequence in LPS/GalN-treated mice and the remarkable decrease in combined HMGB1 protein by GL. The current findings claim that a single injection of LPS/GalN might stimulate apoptosis of hepatocytes through the binding of HMGB1 protein to Gsto1 promoter region and that GL-treatment might prevent the apoptosis and inflammatory infiltrates caused with LPS/GalN-injection by disturbing the binding of HMGB1 protein to Gsto1 promoter sequence.
PLoS ONE 04/2014; 9(4):e92884. DOI:10.1371/journal.pone.0092884 · 3.23 Impact Factor
"Severe developmental and lethal phenotypes are observed upon deletion of NFκB family members that are widely expressed. Disruption of RelA causes embryonic lethality at embryonic day (E) 15.5 secondary to widespread hepatocyte apoptosis, and identified an essential role for NκB in preventing tumor necrosis factor-alpha (TNF-α) induced cell death (Beg et al., 1995b; Beg and Baltimore, 1996). Mice lacking IKKβ phenocopy the RelA−/− mice, dying in utero between E12.5 and E14 as a result of hepatic apoptosis and necrosis, and display impaired activation of NFκB in response to TNF-α and IL-1 (Li et al., 1999b, 1999c). "
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