Loss of SIMPL compromises TNF-α-dependent survival of hematopoietic progenitors

OBJECTIVE: Emerging work has revealed an integral role of the TNFα-NF-κB pathway in the regulation of hematopoiesis. TNFα inhibition of hematopoietic stem/progenitor cell growth involves the type I TNFα receptor (TNF RI) and the type II TNFα receptor (TNF RII). However the role of TNF RI versus TNF RII in mediating this response is less clear. Full induction of NF-κB dependent gene expression through TNF RI requires the transcriptional co-activator SIMPL. To address the role of SIMPL in TNFα dependent signaling in hematopoiesis, endothelial cells and hematopoietic progenitors expressing SIMPL shRNA were characterized. MATERIAL AND METHODS: In vitro gene expression and progenitor assays employing SIMPL shRNA were used to examine the requirement for SIMPL in TNFα dependent effects upon cytokine gene expression and hematopoietic progenitor cell growth. Competitive repopulation studies were used to extend these studies in vivo. RESULTS: SIMPL is required for full TNF RI dependent expression of NF-κB controlled cytokines in endothelial cells. Hematopoietic progenitor cell expansion is not affected if progenitors lacked SIMPL or if progenitors are treated with human TNFα which signals through TNF RI. In the absence of SIMPL, human TNFα leads to a dramatic decrease in progenitor cell expansion that is not due to apoptosis. Loss of SIMPL does not affect the activity of TGF-β1 and IFNγ, other known suppressors of hematopoiesis. CONCLUSIONS: The suppression of myeloid progenitor cell expansion requires signaling through TNF RI and TNF RII. Signals transduced through the TNFα-TNF RI-SIMPL pathway support hematopoietic progenitor cell survival, growth and differentiation

A key role for orexin in panic anxiety

Panic disorder is a severe anxiety disorder with recurrent, debilitating panic attacks. In individuals with panic disorder there is evidence of decreased central gamma-aminobutyric acid (GABA) activity as well as marked increases in autonomic and respiratory responses after intravenous infusions of hypertonic sodium lactate(1-3). In a rat model of panic disorder, chronic inhibition of GABA synthesis in the dorsomedial-perifornical hypothalamus of rats produces anxiety-like states and a similar vulnerability to sodium lactate-induced cardioexcitatory responses(4-9). The dorsomedial-perifornical hypothalamus is enriched in neurons containing orexin (ORX, also known as hypocretin)(10), which have a crucial role in arousal(10,11), vigilance(10) and central autonomic mobilization(12), all of which are key components of panic. Here we show that activation of ORX-synthesizing neurons is necessary for developing a panic-prone state in the rat panic model, and either silencing of the hypothalamic gene encoding ORX (Hcrt) with RNAi or systemic ORX-1 receptor antagonists blocks the panic responses. Moreover, we show that human subjects with panic anxiety have elevated levels of ORX in the cerebrospinal fluid compared to subjects without panic anxiety. Taken together, our results suggest that the ORX system may be involved in the pathophysiology of panic anxiety and that ORX antagonists constitute a potential new treatment strategy for panic disorder. (C) 2010 Nature America, Inc. All rights reserved