Molecular mechanisms of IL‐18BP regulation in DLD‐1 cells: pivotal direct action of the STAT1/GAS axis on the promoter level

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Abstract
Interleukin (IL)‐18, formerly known as interferon (IFN)‐γ‐inducing factor, is a crucial mediator of host defence and inflammation. Control of IL‐18 bioactivity by its endogenous antagonist IL‐18 binding protein (IL‐18BP) is a major objective of immunoregulation. IL‐18BP is strongly up‐regulated by IFN‐γ, thereby establishing a negative feedback mechanism detectable in cell culture and in vivo. Here we sought to investigate in D.L. Dexter (DLD) colon carcinoma cells molecular mechanisms of IL‐18BP induction under the influence of IFN‐γ. Mutational analysis revealed that a proximal γ‐activated sequence (GAS) at the IL‐18BP promoter is of pivotal importance for expression by IFN‐γ‐activated cells. Use of siRNA underscored the essential role of the signal transducer and activator of transcription (STAT)‐1 in this process. Indeed, electrophoretic mobility shift assay and chromatin immunoprecipitation analysis proved STAT1 binding to this particular GAS site. Maximal expression of IL‐18BP was dependent on de novo protein synthesis but unaffected by silencing of interferon regulatory factor‐1. Altogether, data presented herein indicate that direct action of STAT1 on the IL‐18BP promoter at the proximal GAS element is key to IL‐18BP expression by IFN‐γ‐stimulated DLD‐1 colon carcinoma cells.

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