Inhibitors of WNT production and β-catenin activity impair LPS-induced pro-inflammatory cytokine responses. WT mice received IWP-2 (targets the acyltransferase Porcupine) or ICG-001 (disrupts interaction of β-catenin with CBP) at 20 mg/kg, or DMSO as solvent control, 16 hours before challenge with LPS (2 mg/kg). Serum concentrations of inflammatory cytokines (A) in IWP-2 and (B) ICG-001–treated mice at 3 and 1.5 h after LPS challenge, respectively. Data in (A) are from 5 mice per condition analyzed in 2 independent experiments; data in (B) are from 7 mice per group analyzed in 3 independent experiments. Bars with medians represent the 25th and 75th percentile; whiskers represent the minimum and maximum values. Mann-Whitney U test was employed to compare DMSO and inhibitor-treated groups. *P < .05. (C) Mouse splenocyte cultures were stimulated with LPS (1 µg/mL) for the times indicated in the presence or absence of IWP-2 or ICG-001 (10 µM), or DMSO. IL-6 and IL-12/23p40 concentrations in supernatants were analyzed by enzyme-linked immunosorbent assay. Because TNF and IL-10 concentrations in splenocyte culture supernatants were close to or below the detection limit of the assay (not shown), intracellular (D) TNF and (E) IL-10 expression by CD11b⁺F4/80^hi cells was analyzed by flow cytometry. MFI, mean fluorescence intensity. Data are means ± standard error of the mean of cultures from 4 (C) and 3 (D-E) individual mice analyzed in 2 independent experiments. Groups were compared by 2-way ANOVA and Dunnett multiple comparison correction; ^#P = .053, *P < .05, **P < .01, ****P < .0001.