A monocyte-keratinocyte-derived co-culture assay accurately identifies efficacies of BET inhibitors as therapeutic candidates for psoriasiform dermatitis.

BACKGROUND: Bromodomain and extra-terminal (BET) proteins perform key roles in epigenetic control of gene expression that is involved in inflammatory conditions, including psoriasiform dermatitis (PsD). Predicting which (of many potential available BET inhibitors) will be effective in vivo is challenging. OBJECTIVE: We determine if a novel in vitro assay that includes two critical cell types involved in human psoriasis can predict the therapeutic potential of specific BET inhibitors in vivo. METHODS: An in vitro model consisting of U-937 and HaCaT cell co-culture was created to screen small molecule BET antagonists for inhibition of cutaneous inflammatory genes. Efficacious BET inhibitors were tested in a mouse imiquimod (IMQ)-induced PsD model. RESULTS: In the co-culture system, HaCaT cells exhibited a marked increase in the secretion of a characteristic set of proinflammatory and Th17-associated cytokines. Of the ten commercially-available small molecules targeting BET proteins assayed, most compounds exhibited inhibitory functions at 1 µM against inflammatory activation, but responded variably at lower concentrations. OTX015, a typical representative for most of the compounds, barely inhibited the inflammatory reactions at 0.1 µM. By contrast, ABBV075 was effective in concentrations as low as 0.01 µM. While oral administration OTX015 in IMQ-treated mice reduced disease severity, ABBV075 equally decreased the symptoms and molecular and cellular severity markers at one-tenth of the minimal dosing required for OTX015. CONCLUSION: In vitro screening system combined with an in vivo animal model, can serve as a convenient pre-clinical screening tool for the selection of BET inhibitors (and possibly other drugs) that may have clinical potential in psoriasis therapy.

IL-10 is overexpressed in human cutaneous T-cell lymphoma and is required for maximal tumor growth in a mouse model.

A crucial question pertains to a role of IL-10 as a tumorigenic factor, or just a marker of advanced disease in cutaneous T-cell lymphoma (CTCL). Herein, we measured significantly elevated IL-10 mRNA in a cohort of skin samples of patients with CTCL. Increased IL-10 was also detected in the tumor microenvironment of an established inflammation-dependent murine model of using MBL2 T lymphoma cells. Conditioned media from MBL2 cells was able to stimulate IL-10 production in bone marrow-derived macrophages in an IL-4-dependent manner. Implanted MBL2 T-cell lymphomas in IL-10KO mice were 50% smaller, accompanied by decreased numbers of infiltrating macrophages and reduced efficiency of M2-polarization compared with wild-type mice. With anti-IL-10R mAb treatment, both wild-type tumor-bearing mice and IL-10KO mice exhibited a further growth inhibition. Our data indicate that targeting IL-10 signaling with neutralizing antibodies to IL-10 or its receptor may have a great potential for advanced CTCL therapy.