RIPK3 is essential for the cytokine production and ensuing granulocytosis that are caused by the combined loss of cIAPs and XIAP. (A) WT mice were either left untreated (-) or injected intraperitoneally (+) with the Smac mimetic compound Abbott11 (20 mg/kg body weight). After 5 hours, the levels of the cytokines and chemokines indicated were measured by multiplex. (B-C) Mice of the genotypes indicated were either left untreated (-) or injected intraperitoneally (+) with the Smac mimetic compound Abbott11 (20 mg/kg body weight) for 2 weeks (daily for 5 days, then 2 days of rest). (B) The ratios of the spleen weight to total body weight of the mice after injection of Abbott11 were compared with the ratios from untreated control animals. (C) Increased numbers of granulocytes (Ly6G⁺) and macrophages (F4/80⁺) were found in spleens of WT and Tnf^−/− mice injected with Abbott11 but not in Abbott11-injected Ripk3^−/−mice. (D) c1^LCc2^−/−X^−/− mice were injected with anti-TNF (MP6-XT22, 10 mg/kg) for 3 weeks and assessed for changes in granulocyte (Ly6G⁺) and monocyte (F4/80⁺Ly6C^lo and F4/80⁺Ly6C^hi) populations in the peripheral blood. Each point represents an individual mouse. Mean ± SEM are shown. ***P < .001; **P < .01; *P < .05.