IL-36?/IL-1F9, an innate T-bet target in myeloid cells.

ABSTRACT: 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?, a recently described novel IL-1 family member. Promoter analysis revealed a T-bet binding site that, along with a ?B site, enables efficient IL-36? induction. Using knock-out animals, IL-36? reliance on T-bet was extended to murine DC. IL-36? 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? on endogenous T-bet in human primary cells. Ectopic expression of T-bet likewise mediated IL-36? production in HaCaT keratinocytes that otherwise lack this transcription factor. Additional experiments furthermore revealed that mature IL-36? has the capability to establish an inflammatory gene expression profile in human primary keratinocytes that displays enhanced mRNA levels for TNF?, CCL20, S100A7, inducible NOS, and IL-36? itself. Data presented herein shed further light on involvement of T-bet in innate immunity and suggest that IL-36?, besides IFN?, may contribute to functions of this transcription factor in immunopathology.

SUBMITTER: Bachmann M 

PROVIDER: S-EPMC3516718 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature