Data presented may also be relevant

Data presented may also be relevant in the context of acute myeloid leukemia and myelodysplastic syndrome treatment by 5-AzaD (Decitabine) [46]. 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 [49], acute liver injury [50,51], and hemophagocytic lymphohistiocytosis [52]. 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 [53] which may also be relevant for adjuvant therapy by CpG-oligonucleotides. Despite this 54011 receptor clear anti-inflammatory profile of IL-18BP, the possibility of physical interaction with IL-37 must be discussed [54]. IL-37 is regarded an anti-inflammatory deactivator of innate immunity [55]. 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 [56]. 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 [57]. 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 [59]. 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) [60] and human tristetraproline [61]. 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. The following is the supplementary data related to this article.
Funding This work was supported by departmental funding to Prof. Mühl. Funding derived from the State of Hessia to the Institute of General Pharmacology and Toxicology at the pharmazentrum frankfurt (Head: Prof. Josef Pfeilschifter).