BRD6989 Inhibits CDK8 and Enhances IL-10 Production

By Edward Jenner 2019-12-24 #CDK8, #IL-10

The cytokine IL-10 promotes immune homeostasis via multiple mechanisms. It includes suppressing inflammatory cytokine production by innate immune cells and by promoting regulatory T cell (Treg) function.

Loss-of-function mutations in IL-10 or its receptor may result in severe, pediatric-onset enterocolitis. It has been proved that IL-10-based therapy can release symptoms in murine models of colitis and arthritis. In addition, recombinant IL-10 (rIL-10) with oral administration or injection has shown promise in clinical trials for Crohn’s disease and rheumatoid arthritis, respectively.

Small-molecule probes provide key insights into the regulation of IL-10 in innate immune cells.

In this article, we will introduce BRD6989, an analog of the natural product Cortistatin A (DCA).

BRD6989 inhibits CDK8 and can upregulate IL-10 in activated human and mouse dendritic cells. At the same time, this effect requires an intact cyclin C-CDK8 complex.

Firstly, in BMDCs, BRD6989 pretreatment after the stimulation with the yeast cell wall extract Zymosan A increases IL-10 production. It exhibits an EC₅₀ value of 1 μM. Meanwhile, only modestly cell viability is reduced in these assay conditions.

Additionally, BRD6989 suppresses Zymosan A-induced release of the inflammatory cytokine IL-6, However, left the production of TNFα, IL-12p40, and IL-1β largely remain unchanged.

BRD6989 induces a similar cytokine response in BMDCs with the viral RNA mimetic R848 but possesses a greater fold increase in IL-10 production.

Nextly, Except for BMDCs, BRD6989 also increases IL-10 production in mouse bone-marrow-derived macrophages (BMDMs) activated with zymosan A or R848.

lastly, in human monocyte-derived DCs from two independent donors, BRD6989 upregulates IL-10production after R848 stimulation at various concentrations. BRD6989 suppresses phosphorylation of the STAT1 transactivation domain at Ser727 in IFNγ-stimulated BMDCs.
In summary, BRD6989 enhances IL-10 production in activated human and murine macrophages and dendritic cells by a mechanism, which appears to be particularly prominent after stimulation of toll-like receptor-7 (TLR7) and TLR8 by R848.