Data presented herein suggest that
Data presented herein suggest that competent IL-18BP production in epithelial Gardiquimod is implemented by epigenetic means based on demethylation of a single CpG site at −45 bp/−44 bp (CpG2) of the human IL18BP promoter. In contrast, retarded IL-18BP production in monocytic cells associates with CpG2 methylation. Pharmacological CpG2 demethylation in monocytic cells in fact hindered binding of MeCP2 to CpG2 which not only connected to enhanced IL-18BP expression but also to an increased frequency of H3K9ac at this location and to enforced recruitment of RNA-polymerase-II to the nearby IL18BP transcriptional start site. Both latter observations evidently indicate an increasingly active [30,31,35] IL18BP gene locus under conditions of demethylation. Notably, STAT1 binding to the critical GAS site of the IL18BP promoter was not affected by 5-AzaD mediated demethylation. This novel epigenetic aspect of human IL-18BP regulation may serve and control important IL-18-related cell type-specific (patho)-physiological functions. Efficient IL-18BP production by epithelial cells may counteract surplus epithelial IL-18 that otherwise should support pathological inflammation at host/environment interfaces. Notably, intestinal epithelial cells are a significant source of biologically active IL-18 . Vice versa, silencing of the IL18BP locus by CpG methylation ensures adequate generation of monocyte-derived IL-18 biological activity. This should be crucial for the key function of monocytes to combat infections in the blood. Interestingly, monocytes display primed caspase-1  which is supposed to enable rapid release of demanded bioactive IL-18 during systemic infections. Accordingly, a decisive role for IL-18 in host defense is evident in the context of septic conditions [, , ]. Data presented may also be relevant in the context of acute myeloid leukemia and myelodysplastic syndrome treatment by 5-AzaD (Decitabine) . In fact, IL-18 has been implicated in the pathogenesis of both hematologic malignancies [47,48] which suggests reinforcement of IL-18BP as potential aspect of 5-AzaD therapeutic value in these diseases. Therapeutic efficacy in murine models of inflammatory diseases classifies IL-18BP as anti-inflammatory. Those include e.g. experimental colitis , acute liver injury [50,51], and hemophagocytic lymphohistiocytosis . Interestingly, in closely related murine macrophage activation syndrome triggered by the CpG-oligonucleotide/TLR9 axis, onset and severity of disease as well as production of IFNγ and CXCL9 is tightly controlled by endogenous IL-18BP  which may also be relevant for adjuvant therapy by CpG-oligonucleotides. Despite this clear anti-inflammatory profile of IL-18BP, the possibility of physical interaction with IL-37 must be discussed . IL-37 is regarded an anti-inflammatory deactivator of innate immunity . Since mice apparently lost il37, this interaction is lacking in murine disease models. In humans, however, high concentrations of IL-18BP may interfere with IL-37 activity thereby possibly counteracting its anti-inflammatory action. This scenario is discussed particularly in the context of clinical therapy by recombinant IL-18BP . Whether endogenous IL-18BP levels achievable in human diseases are actually sufficient to enable functionally relevant interaction with IL-37 is, however, uncertain. Notably, recombinant IL-18BP (tadekinig-α), recently evaluated in a phase II clinical trial for treatment of adult onset still's disease patients, shows evident anti-inflammatory action as detected e.g. by serum C-reactive protein . It is intriguing to note that herein proposed IL18BP regulation by methylation of a single CpG at −44 bp/−45 bp displays striking coincidence with silencing of the IFNG gene in developing Th2 cells where methylation of a single CpG at −53 bp/−52 bp is crucial [58,59]. In that latter case, however, CpG methylation directly interferes with promoter binding of the transcription factors ‘cAMP response element-binding protein’ (CREB), ‘activating transcription factor-2’ (ATF2), and c-Jun, apparently without requirement of histone modifications . Single CpG-dependent epigenetic inhibition of gene expression as detected herein is exceptional but was observed for murine ‘receptor activator of NF-κB ligand’ (RANKL)  and human tristetraproline . There, in similarity to current results regarding human IL18BP, methylation of a single CpG results in recruitment of methyl-CpG-binding proteins (such as methyl-CpG-binding protein-2 and/or methyl-CpG-binding domain protein-2) and associated histone deacetylation.