A critical role for p53 in the control of NF-kappa B-dependent gene expression in TLR4-stimulated dendritic cells exposed to genistein

Considerable research has focused on the anti-inflammatory and antiproliferative activities exhibited by the soy isoflavone genistein. We previously demonstrated that genistein suppresses TNF-alpha-induced NF-kappaB-dependent IL-6 gene expression in cancer cells by interfering with the mitogen- and stress-activated protein kinase 1 activation pathway. However, effects of isoflavones on immune cells, such as dendritic cells, remain largely unknown. Here we show that genistein markedly reduces IL-6 cytokine production and transcription in LPS-stimulated human monocyte-derived dendritic cells. More particularly, we observe that genistein inhibits IL-6 gene expression by modulating the transcription factor NF-kappaB. Examination of NF-kappaB-related events downstream of TLR4 demonstrates that genistein affects NF-kappaB subcellular localization and DNA binding, although we observe only a minor inhibitory impact of genistein on the classical LPS-induced signaling steps. Interestingly, we find that genistein significantly increases p53 protein levels. We also show that overexpression of p53 in TLR4/MD2 HEK293T cells blocks LPS-induced NF-kappaB-dependent gene transcription, indicating the occurrence of functional cross-talk between p53 and NF-kappaB. Moreover, analysis of IL-6 mRNA levels in bone marrow-derived p53 null vs wild-type dendritic cells confirms a role for p53 in the reduction of NF-kappaB-dependent gene expression, mediated by genistein.info:eu-repo/semantics/publishe

Feasibility study for clinical application of caspase-3 inhibitors in Pemphigus vulgaris.

The potentially severe side effects of systemic corticosteroids and immunosuppressants used in Pemphigus vulgaris (PV) call for novel therapeutic approaches. In this context, pharmacological inhibition of major pathogenic signalling effectors represents a promising alternative. However, we have also shown that overinhibition of effectors required for epidermal homeostasis can exacerbate PV pathophysiology implicating transepidermal keratinocyte fragility. A feedforward target validation therefore preferentially includes studies on knockout mouse models. We previously reported on successful amelioration of PV blisters following inhibition of non-apoptotic, low-level caspase-3. Here, we use conditional, keratinocyte-specific caspase-3-deficient mice (casp3EKO ) to demonstrate (i) absence of keratinocyte fragility upon injection of the potent Dsg3-specific antibody AK23 and (ii) amelioration of blistering on the background of known signalling effectors. Our results provide the experimental proof of concept justifying translation of the caspase-3 inhibitor approach into PV clinical trials

A System Architecture for Wireless Building Automation

Abstract — Wireless Building Automation is a complex problem dealing with a lot of trade offs: on one hand sensors and actuators have to be as energy-efficient as possible, while on the other hand the overall network should be performant and resilient enough to extend or even replace a wired backbone. In addition, the network should be able to serve existing IEEE 802.11 devices such as PDAs, cameras and laptops. Furthermore, surveillance, fire detection and other critical building automation applications require end-to-end Quality of Service support to ensure the bandwidth and delay requirements also in the case of high network loads. A networking technology that simultaneously fulfills all those requirements does not exist. This paper introduces a system architecture that combines heterogeneous technologies into an appropriate networking solution. I