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RIPK1 coordinates TNF signaling through kinase-dependent and -independent mechanisms. S161 autophosphorylation is a primary function of RIPK1 kinase activity in vitro, and here we show that it is sufficient to mediate RIPK1 kinase\u2013dependent function in vivo. S161 phospho-mimic mutation (S161E) effectively overcomes chemical or genetic inhibition of RIPK1 kinase activity in TNF-treated cells and mice. Mechanistically, S161 autophosphorylation is necessary for further autophosphorylation in RIPK1, including at S166. Ripk1S161E\/S161E mice are hypersensitive to TNF, enabling us to observe low-dose TNF-induced necroptosis in cecal intestinal epithelial cells (IECs) and endothelial cells (ECs) and uncover a reciprocal enhancement between IEC and EC necroptosis and a selective increase of IL-6 in the circulation by necroptosis. IL-6 promotes cecal edema and synergizes with IEC and EC necroptosis, causing cecal damage and mouse death. 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