Kubicek, S

Kubicek, S., R. epigenetic dysregulation involving interactions between histone deacetylation and hypermethylation is responsible for targeted repression of IP-10 and potentially other antifibrotic genes in fibrotic lung disease and that this is amenable to therapeutic targeting. Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease characterized by exaggerated extracellular matrix deposition and aggressive structural remodeling. The prognosis of IPF is poor, with less than a 50% 5-year survival rate, the etiology of the disease remains unknown, and the main therapies of antiinflammatory corticosteroids and immunosuppressive agents are ineffective (6, 21). It is therefore essential that the mechanisms that orchestrate this disease are defined to allow the development of novel, targeted, and effective therapeutic options. Angiogenesis is critical in physiological and pathological processes such as wound healing, tumor growth, and inflammation (32). There is evidence that aberrant angiogenesis may be an important factor in supporting MC-Val-Cit-PAB-Indibulin tissue remodeling and contribute to IPF in a manner similar to that seen in tumorigenesis (39). Angiogenesis is a highly coordinated process that is regulated by an opposing balance between locally produced angiogenic and angiostatic molecules. However, an imbalance in the levels of angiogenic and angiostatic chemokines that favors net angiogenesis has been shown in animal models and tissue specimens from patients with IPF (11-14). The CXC chemokine gamma interferon (IFN-)-inducible protein of MDK 10 kDa (IP-10; CXCL10) is a potent chemoattractant for mononuclear leukocytes and a strong inhibitor of angiogenesis (40). Recent studies have demonstrated that lung tissues from IPF patients and isolated fibroblasts from IPF patients (F-IPF) constitutively express less IP-10 and more interleukin-8 (IL-8), thereby inducing greater angiogenic activity than tissues from control MC-Val-Cit-PAB-Indibulin subjects and fibroblasts from nonfibrotic lungs (F-NL) (12). Furthermore, lung tissue from a murine model of bleomycin-induced pulmonary fibrosis demonstrates a significant decrease in IP-10, which is inversely correlated to total lung collagen and a greater angiogenic response than that from controls (13). Collectively, these findings suggest that IP-10 is an important regulatory molecule in angiogenesis as well as fibroblast migration and proliferation. Therefore, repression of IP-10 may play a key role in the aberrant tissue remodeling and the development of IPF and other fibrotic diseases. However, the molecular mechanisms for repressed IP-10 expression in IPF have not been explored. The 5-flanking promoter region of human IP-10 contains multiple regulatory elements, including two interferon-stimulated responsive element (ISRE), two signal transducer and activator of transcription (STAT), two CCAAT/enhancer-binding protein (C/EBP-), and two nuclear factor B (NF-B)-binding sites (38). Induction of IP-10 in response to cytokines is dependent primarily on transcription (28, 29), which is critically governed by various transcription factors in a cell-type-specific and stimulus-specific manner. IFN-induced IP-10 transcription is characteristically mediated by the transcription factors IFN MC-Val-Cit-PAB-Indibulin regulatory factor 1 (IRF-1), p48, and STAT-1 via ISRE, whereas IL– and tumor necrosis factor alpha (TNF-)-induced IP-10 transcription is typically mediated by NF-B (5, 23, 46). Posttranslational modifications of histone proteins in chromatin structure play a central role in the epigenetic regulation of gene transcription. Histone acetylation and methylation are the two most common and best-characterized modifications that function as specific transcription regulators. Histone acetylation on lysine residues by histone acetyltransferases (HATs) and histone deacetylation by histone deacetylases (HDACs) are associated with transcriptional activation and repression, respectively. Several transcription coactivators, including p300, CREB binding protein (CBP), p300/CBP-associated MC-Val-Cit-PAB-Indibulin factor (PCAF), and general control nonderepressible 5 (GCN5), have been found to possess intrinsic HAT.