title: IL-36γ/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-36γ, a recently described novel IL-1 family member. Promoter analysis revealed a T-bet binding site that, along with a κB site, enables efficient IL-36γ induction. Using knock-out animals, IL-36γ reliance on T-bet was extended to murine DC. IL-36γ expression by human myeloid cells was confirmed using monocyte-derived DC and M1 macrophages. The latter model was employed to substantiate dependence of IL-36γ on endogenous T-bet in human primary cells. Ectopic expression of T-bet likewise mediated IL-36γ production in HaCaT keratinocytes that otherwise lack this transcription factor. Additional experiments furthermore revealed that mature IL-36γ has the capability to establish an inflammatory gene expression profile in human primary keratinocytes that displays enhanced mRNA levels for TNFα, CCL20, S100A7, inducible NOS, and IL-36γ itself. Data presented herein shed further light on involvement of T-bet in innate immunity and suggest that IL-36γ, besides IFNγ, may contribute to functions of this transcription factor in immunopathology.
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, University Hospital, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Bachmann
authors.forename: Patrick
authors.initials: P
authors.lastname: Scheiermann
authors.forename: Lorena
authors.initials: L
authors.lastname: Härdle
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.forename: Heiko
authors.initials: H
authors.lastname: Mühl
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020218:Response Elements / Q000502:physiology*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: C569167:IL1F9 protein, mouse; C508589:IL36G protein, human; D007375:Interleukin-1; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor