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necrosome'

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-like aggregates, is a critical step in direct- ing RIPK1 and RIPK3 kinase-mediated in?ammation. Finally, we have extended our observations in vivo, af?rming the impor- tance of RIPK1 and RIPK3 kinases in the global regulation of acute in?ammation induced by a sub-lethal dose of LPS in the absence of exogenous caspase-8 inhibition. RESULTS RIPK1 and RIPK3 Kinases Promote LPS-Induced In?ammatory Gene Expression in the Absence of Caspase-8 Activation Previously published work suggests that kinase activity of RIPK1 does not contribute to the pro-in?ammatory regulation by TLR4 in response to LPS (Cusson-Hermance et al., 2005;

Meylan et al., 2004;

Newton et al., 2004;

Vivarelli et al., 2004). However, the activation of RIPK1 kinase activity and necroptosis also does not occur in LPS-treated macrophages, unless cas- pases are inhibited using the pan-caspase inhibitor zV........