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Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract. Cytokines have a critical role in the pathogenesis of IBD, in which they control multiple aspects of the inflammatory response. One such cytokine, Interleukin (IL-36) is overexpressed in both experimental and human IBD and may play both pathogenic and protective roles, depending on the context. The IL-36 signaling pathway induces IL-22, a cytokine that is critical in repair and regeneration of the gut epithelium during inflammation. However, the mechanism by which IL-36 induces IL-22 and promotes barrier repair is incompletely understood. We observed a cytokine network, in which, IL-36γ/IL-36R signaling is an important upstream driver of IL-22 and antimicrobial peptide (AMP) production to protect the host against acute intestinal damage. We have shown that IL-36γ is a potent inducer of IL-23. IL-36γ–induced IL-23 requires Notch2-dependent dendritic cells (DCs). The intracellular signaling cascade linking IL-36 receptor (IL-36R) to IL-23 production by DCs involved MyD88 and the NF-κB subunits. Consistent with in vitro observations, IL-36R-/- mice exhibited dramatically reduced IL-23, IL-22, and AMP levels, and consequently failed to recover from acute intestinal damage. Interestingly, impaired recovery of mice deficient in IL-36R was rescued by treatment with exogenous IL-23. We also found that IL-36R-/- mice are defective of host protection during enteropathogenic bacterial infection. The IL-36 signaling cascade is essential in both early and late phases of immune defense against C. rodentium infection. During the early stage of infection, IL-36 induced the production of IL-22 by innate lymphoid cells 3 (ILC3s) via IL-23; and during the late phase, IL-36 stimulated the production of IL-22 from T-cells via IL-6. Intriguingly, in the experimental chronic colitis, IL-36R-/- mice display reduced disease severity and are associated with decreased production of inflammatory cytokines and enhance expression of Foxp3 regulatory T cells. Collectively, these findings highlight context-dependent, protective and pathogenic contribution of the IL-36R signaling pathway and the potential for optimally manipulating this pathway for better treatment of intestinal inflammation.

Histones are modified by enzymes that act in a locus, cell-type, and developmental stage-specific manner. The recruitment of enzymes to chromatin is regulated at multiple levels, including interaction with sequence-specific DNA-binding factors. However, the DNA-binding specificity of the regulatory factors that orchestrate specific histone modifications has not been broadly mapped. We have analyzed 6 histone marks (H3K4me1, H3K4me3, H3K27ac, H3K27me3, K3H9me3, H3K36me3) across 121 human cell types and tissues from the NIH Roadmap Epigenomics Project as well as 8 histone marks (with the addition of H3K4me2 and H3K9ac) from the mouse ENCODE Consortium. We have identified 361 and 369 DNA motifs in human and mouse, respectively, that are the most predictive of each histone mark. Interestingly, 107 human motifs are conserved between the two species. In human embryonic cell line H1, we mutated only the found DNA motifs at particular loci and the significant reduction of H3K27ac levels validated the regulatory roles of the perturbed motifs. The functionality of these motifs was also supported by the evidence that histone-associated motifs, especially H3K4me3 motifs, significantly overlap with the expression of quantitative trait loci SNPs in cancer patients more than the known and random motifs. Furthermore, we observed possible feedbacks to control chromatin dynamics as the found motifs appear in the promoters or enhancers associated with various histone modification enzymes. These results pave the way toward revealing the molecular mechanisms of epigenetic events, such as histone modification dynamics and epigenetic priming.