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Receptor interacting protein kinase 1 (RIPK1) has important kinase-dependent and kinase-independent scaffolding functions that activate or prevent apoptosis or necroptosis in a cell context-dependent manner. The kinase activity of RIPK1 mediates hypothermia and lethality in a mouse model of TNF-induced shock, reflecting the hyperinflammatory state of systemic inflammatory response syndrome (SIRS), where the proinflammatory 'cytokine storm' has long been viewed as detrimental. Here, we demonstrate that cytokine and chemokine levels did not predict survival and, importantly, that kinase- inactive [Ripk1.sup.D138N/D138N] hematopoietic cells afforded little protection from TNF- or TNF/zVAD-induced shock in reconstituted mice. Unexpectedly, RIPK1 kinase-inactive mice transplanted with WT hematopoietic cells remained resistant to TNF-induced shock, revealing that a nonhematopoietic lineage mediated protection. TNF-treated [Ripk1.sup.D138N/D138N] mice exhibited no significant increases in intestinal or vascular permeability, nor did they activate the clotting cascade. We show that TNF administration damaged the liver vascular endothelium and induced phosphorylated mixed lineage kinase domain-like (phospho-MLKL) reactivity in endothelial cells isolated from TNF/zVAD-treated WT, but not [Ripk1.sup.D138N/D138N], mice. These data reveal that the tissue damage present in this SIRS model is reflected, in part, by breaks in the vasculature due to endothelial cell necroptosis and thereby predict that RIPK1 kinase inhibitors may provide clinical benefit to shock and/or sepsis patients., Introduction The serine/threonine receptor interacting protein kinase 1 (RIPK1) plays a prominent role in proinflammatory and cell-survival signaling by mediating optimal NF-[kappa]B and MAPK pathway activation downstream of TNF and [...]

Lymphedema, the most common lymphatic anomaly, involves defective lymphatic valve development; yet the epigenetic modifiers underlying lymphatic valve morphogenesis remain elusive. Here, we showed that during mouse development, the histone-modifying enzyme histone deacetylase 3 (Hdac3) regulates the formation of both lymphovenous valves, which maintain the separation of the blood and lymphatic vascular systems, and the lymphatic valves. Endothelium-specific ablation of Hdac3 in mice led to blood-filled lymphatic vessels, edema, defective lymphovenous valve morphogenesis, improper lymphatic drainage, defective lymphatic valve maturation, and complete lethality. Hdac3-deficient lymphovenous valves and lymphatic vessels exhibited reduced expression of the transcription factor Gata2 and its target genes. In response to oscillatory shear stress, the transcription factors Tal1, Gata2, and Ets1/2 physically interacted with and recruited Hdac3 to the evolutionarily conserved E-box-GATA-ETS composite element of a Gata2 intragenic enhancer. In turn, Hdac3 recruited histone acetyltransferase Ep300 to form an enhanceosome complex that promoted Gata2 expression. Together, these results identify Hdac3 as a key epigenetic modifier that maintains blood-lymph separation and integrates both extrinsic forces and intrinsic cues to regulate lymphatic valve development., Introduction Thin-walled lymphatic capillaries collect interstitial fluid (lymph) and transport it via collecting lymphatic vessels to the thoracic duct, which in turn drains into the subclavian vein (1). Improper drainage [...]

The hypoxia inducible factors (HIFs) and CCAAT/enhancer binding protein alpha (C/EBP alpha) are transcription factors that mediate adaptive responses to hypoxia and control aspects of energy metabolism, respectively. New evidence suggests that when HIF-1 alpha and C/EBP alpha interact, they bring about reciprocal functional changes, so that the activity of HIF-1 alpha is decreased and that of C/EBP alpha is restricted or increased in a tissue-specific manner. This Journal Club article highlights research depicting interactions between HIF-1 alpha and C/EBP alpha and discusses conditions and tissues in which this interaction might occur.