We evaluated the effect of gut bacterial metabolites of polyunsaturated fatty acids on inflammation and found that 10-oxo-cis-6,trans-11-octadecadienoic acid (gamma KetoC) strikingly suppressed LPS-induced IL-6 release from bone marrow-derived macrophages (BMMs), which was accompanied by reduced mRNA expression of Il6, TNF, and Il1b. gamma KetoC decreased the cAMP concentration in BMMs, suggesting that gamma KetoC stimulated G protein-coupled receptors. A Gq agonist significantly suppressed LPS-induced IL-6 expression in BMMs, whereas a Gi inhibitor partially abrogated gamma KetoC-mediated IL-6 suppression. Cytosolic Ca2+ was markedly increased by gamma KetoC, which was partly but not fully abrogated by an ion channel inhibitor. Taken together, these data suggest that gamma KetoC suppresses inflammatory cytokine expression in macrophages primarily through Gq and partially through Gi. gamma KetoC suppressed osteoclast development and IL-6 expression in synovial fibroblasts from rheumatoid arthritis (RA) patients, suggesting the beneficial effect of gamma KetoC on the prevention or treatment of RA. (c) 2020 Elsevier Inc. All rights reserved.