Inflammatory Bowel Disease(IBD) is characterised by increased numbers of newly recruited monocytes to the intestinal mucosa, where they release several proinflammatory cytokines. Among these is interleukin-8(IL-8), a potent neutrophil attractant that is important in driving the initiation and perpetuation of IBD. Although IBD is associated with alterations in the colonic bile acid pool, the role that bile acids play in regulating innate immunity is still poorly understood. Thus, the aim of this study was to investigate the effects of the naturally-occurring colonic bile acids, ursodeoxycholic acid(UDCA) and deoxycholic acid(DCA), on IL-8 secretion from U937 monocytes. IL-8 release from U937 monocytes was induced with lipopolysaccharide(LPS) [1µg/mL] or the proinflammatory cytokine,TNFα [5ng/mL]for 24hrs. Cells were co-treated with either UDCA or DCA. Supernatants were analysed for IL-8 protein by ELISA. IL-8 mRNA was assessed by qPCR. Cytotoxic effects of bile acids were determined by detection of lactate dehydrogenase release. Statistical analysis was performed using one way ANOVA with the Newman-Keuls post test. Treatment of U937 monocytes with TNFα and LPS induced a 9.8±1.2 and 7.9±1.6 fold increase in IL-8 release,respectively, compared to untreated controls(n=5-7;p<0.001). UDCA, at concentrations of 25, 50 and 100µM, reduced TNFα-induced IL-8 release to 5.3± 0.8,4.9±0.6 and 3.5±0.4 fold, respectively(n=5;p<0.001). UDCA had no effect on LPS-driven IL-8 release. UDCA attenuation of IL-8 release occurred at the mRNA level(n=4;p< 0.05). DCA, at concentrations of 10,25 and 50µM, also inhibited TNFα-stimulated IL-8 release to 4.7±1.2, 4.6±0.4 and 3.9±0.9 fold, respectively (n=5;p<0.001).Furthermore, DCA [10,25 and 50µM] also attenuated LPS-driven IL-8 release to 5.1±0.8,4.2±0.6 and 4.3 ±0.5 fold, respectively(n=7;p<0.05).Neither UDCA nor DCA exerted toxic actions at any of the concentrations employed(n=3).Finally, activation of the bile acid receptors, TGR5 or FXR, with the specific agonists INT-777[50µM] and GW4064[1µM], respectively, had no effect on either TNFα or LPS-induced IL-8 release(n=4). The results of this study demonstrate that the naturally-occurring bile acids, UDCA and DCA inhibit proinflammatory cytokine release from monocytes in vitro. While DCA inhibits both TNFα and LPS-driven IL-8 release, UDCA is specific for inhibition of the TNFα-driven pathway. This indicates that there are likely to be distinct mechanisms of action for the bile acids, although neither involves TGR5 or FXR activation. Overall, by virtue of their capacity to downregulate cytokine release from monocytes, our data suggest that bile acids may exert anti-inflammatory actions in vivo and may therefore prove to be useful targets for developing new therapies for IBD.