IL-10 is an anti-inflammatory cytokine that limits immune activation of innate and adaptive immune cells. IL-10 signaling plays a crucial role in modulating mucosal inflammation in the intestine, and deletion of the cytokine or its receptor (IL-10R) results in severe inflammatory bowel disease (IBD) in both mice and humans. Despite the importance of IL-10 in maintaining intestinal homeostasis, the exact mechanism by which IL-10-IL-10R signaling reduces inflammation is not well understood. Accumulated work has revealed that inflammatory signals rapidly rewire lipid metabolic programs of immune cells to support inflammation and effector functions, leading to the hypothesis that anti-inflammatory cytokines such as IL-10 may direct changes in lipid metabolism to counteract inflammatory stimuli. This study tests this hypothesis and uncovers a role for IL-10 signaling in the regulation of sphingolipid metabolism in macrophages downstream of toll-like receptor 2 (TLR2). In the absence of IL-10, TLR2-activated macrophages have increased metabolic flux through the de novo sphingolipid biosynthesis pathway, resulting in the accumulation of endogenously synthesized ceramides. Increased levels of saturated very long chain (VLC) ceramides specifically contributed to inflammatory phenotypes both in vitro and in vivo. Surprisingly, altered sphingolipid metabolism in IL-10 deficient cells was mediated by reduced synthesis of mono-unsaturated fatty acids (MUFAs), and could be corrected by providing exogenous MUFAs. The prolonged inflammatory gene expression programme enforced by altered VLC ceramide homeostasis requires the NF-κB family transcription factor REL. These studies provide strong evidence that coordinate regulation of lipid metabolism by IL-10 is necessary to constrain REL-dependent pathologic inflammation and suggest that targeting specific aspects of lipid homeostasis in the intestine could control aberrant inflammation underlying IBD. IL-10 signaling regulates sphingolipid metabolism in macrophages in response to inflammatory stimuli both in vitro and in vivo. Loss of VLC ceramides limits inflammation. The length of the variable acyl tail incorporated into ceramides is specified during de novo synthesis by ceramide synthases (CerS). In mouse and humans, there are six ceramide synthases (CerS1–6). RNA-seq data from naive and TLR2-activated wild-type and Il10-KO macrophages showed that BMDMs highly express Cers2, Cers5 and Cers6. Loss of CerS2 in TLR2-activated macrophages disrupts VLC ceramide and sphingomyelin homeostasis. To determine whether CerS2 and its sphingolipid products are important for inflammation, BMDMs from wild-type and Cers2-KO mice were activated with TLR2 ligand. CIL-10 is an anti-inflammatory cytokine that limits immune activation of innate and adaptive immune cells. IL-10 signaling plays a crucial role in modulating mucosal inflammation in the intestine, and deletion of the cytokine or its receptor (IL-10R) results in severe inflammatory bowel disease (IBD) in both mice and humans. Despite the importance of IL-10 in maintaining intestinal homeostasis, the exact mechanism by which IL-10-IL-10R signaling reduces inflammation is not well understood. Accumulated work has revealed that inflammatory signals rapidly rewire lipid metabolic programs of immune cells to support inflammation and effector functions, leading to the hypothesis that anti-inflammatory cytokines such as IL-10 may direct changes in lipid metabolism to counteract inflammatory stimuli. This study tests this hypothesis and uncovers a role for IL-10 signaling in the regulation of sphingolipid metabolism in macrophages downstream of toll-like receptor 2 (TLR2). In the absence of IL-10, TLR2-activated macrophages have increased metabolic flux through the de novo sphingolipid biosynthesis pathway, resulting in the accumulation of endogenously synthesized ceramides. Increased levels of saturated very long chain (VLC) ceramides specifically contributed to inflammatory phenotypes both in vitro and in vivo. Surprisingly, altered sphingolipid metabolism in IL-10 deficient cells was mediated by reduced synthesis of mono-unsaturated fatty acids (MUFAs), and could be corrected by providing exogenous MUFAs. The prolonged inflammatory gene expression programme enforced by altered VLC ceramide homeostasis requires the NF-κB family transcription factor REL. These studies provide strong evidence that coordinate regulation of lipid metabolism by IL-10 is necessary to constrain REL-dependent pathologic inflammation and suggest that targeting specific aspects of lipid homeostasis in the intestine could control aberrant inflammation underlying IBD. IL-10 signaling regulates sphingolipid metabolism in macrophages in response to inflammatory stimuli both in vitro and in vivo. Loss of VLC ceramides limits inflammation. The length of the variable acyl tail incorporated into ceramides is specified during de novo synthesis by ceramide synthases (CerS). In mouse and humans, there are six ceramide synthases (CerS1–6). RNA-seq data from naive and TLR2-activated wild-type and Il10-KO macrophages showed that BMDMs highly express Cers2, Cers5 and Cers6. Loss of CerS2 in TLR2-activated macrophages disrupts VLC ceramide and sphingomyelin homeostasis. To determine whether CerS2 and its sphingolipid products are important for inflammation, BMDMs from wild-type and Cers2-KO mice were activated with TLR2 ligand. C