IL-36γ/IL-1F9, an Innate T-bet Target in Myeloid Cells

By concerted action in dendritic (DC) and T cells, T-box expressed in T cells (T-bet, Tbx21) is pivotal for initiation and perpetuation of Th1 immunity. Identification of novel T-bet-regulated genes is crucial for further understanding the biology of this transcription factor. By combining siRNA technology with genome-wide mRNA expression analysis, we sought to identify new T-bet-regulated genes in predendritic KG1 cells activated by IL-18. One gene robustly dependent on T-bet was IL-36 gamma, a recently described novel IL-1 family member. Promoter analysis revealed a T-bet binding site that, along with a kappa B site, enables efficient IL-36 gamma induction. Using knock-out animals, IL-36 gamma reliance on T-bet was extended to murine DC. IL-36 gamma expression by human myeloid cells was confirmed using monocyte-derived DC and M1 macrophages. The latter model was employed to substantiate dependence of IL-36 gamma on endogenous T-bet in human primary cells. Ectopic expression of T-bet likewise mediated IL-36 gamma production in HaCaT keratinocytes that otherwise lack this transcription factor. Additional experiments furthermore revealed that mature IL-36 gamma has the capability to establish an inflammatory gene expression profile in human primary keratinocytes that displays enhanced mRNA levels for TNF alpha, CCL20, S100A7, inducible NOS, and IL-36 gamma itself. Data presented herein shed further light on involvement of T-bet in innate immunity and suggest that IL-36 gamma, besides IFN gamma, may contribute to functions of this transcription factor in immunopathology.