IL-10 regulates Il12b expression via histone deacetylation: implications for intestinal macrophage homeostasis.

To prevent excessive inflammatory responses to commensal microbes, intestinal macrophages, unlike their systemic counterparts, do not produce inflammatory cytokines in response to enteric bacteria. Consequently, loss of macrophage tolerance to the enteric microbiota plays a central role in the pathogenesis of inflammatory bowel diseases. Therefore, we examined whether the hyporesponsive phenotype of intestinal macrophages is programmed by prior exposure to the microbiota. IL-10, but not in vivo exposure to the microbiota, programs intestinal macrophage tolerance, because wild-type (WT) colonic macrophages from germ-free and specific pathogen-free (SPF)-derived mice produce IL-10, but not IL-12 p40, when activated with enteric bacteria. Basal and activated IL-10 expression is mediated through a MyD88-dependent pathway. Conversely, colonic macrophages from germ-free and SPF-derived colitis-prone Il10(-/-) mice demonstrated robust production of IL-12 p40. Next, mechanisms through which IL-10 inhibits Il12b expression were investigated. Although Il12b mRNA was transiently induced in LPS-activated WT bone marrow-derived macrophages (BMDMs), expression persisted in Il10(-/-) BMDMs. There were no differences in nucleosome remodeling, mRNA stability, NF-κB activation, or MAPK signaling to explain prolonged transcription of Il12b in Il10(-/-) BMDMs. However, acetylated histone H4 transiently associated with the Il12b promoter in WT BMDMs, whereas association of these factors was prolonged in Il10(-/-) BMDMs. Experiments using histone deacetylase (HDAC) inhibitors and HDAC3 short hairpin RNA indicate that HDAC3 is involved in histone deacetylation of the Il12b promoter by IL-10. These results suggest that histone deacetylation on the Il12b promoter by HDAC3 mediates homeostatic effects of IL-10 in macrophages.

Markers of Hypoxia Correlate with Histologic and Endoscopic Severity of Colitis in Inflammatory Bowel Disease.

BACKGROUND: Inflammation results in significant shifts in tissue metabolism. Recent studies indicate that inflammation and hypoxia occur concomitantly. We examined whether circulating and tissue markers of hypoxia could serve as surrogate indicators of disease severity in adult and pediatric patients with inflammatory bowel disease (IBD). METHODS: Serum and colonic biopsies were obtained from pediatric subjects with active IBD colitis and adult subjects with active and inactive ulcerative colitis, along with healthy non-colitis controls of all ages. Disease activity was evaluated by endoscopy and histopathology. Levels of serum hypoxia markers (macrophage inflammatory protein-3α [MIP-3α], vascular endothelial growth factor [VEGF], and erythropoietin [EPO]) were measured. RESULTS: Children with active IBD colitis had higher levels of serum MIP-3α and VEGF compared to non-colitis controls (p<0.01 and p<0.05, respectively). In adult subjects with endoscopically active ulcerative colitis, serum MIP-3α and EPO were significantly elevated compared to non-colitis controls (both p<0.01). In parallel, analysis of colon tissue MIP-3α mRNA and protein in pediatric subjects revealed increased expression in those with IBD colitis compared to controls (p<0.05 and p<0.01 for mRNA and protein, respectively). Serum MIP-3α and VEGF significantly increased with histology grade. CONCLUSION: Peripheral blood hypoxia markers may be useful indicators of disease activity for pediatric and adult IBD patients.