PAI-1 augments mucosal damage in colitis

Abstract

There is a major unmet clinical need to identify pathways in inflammatory bowel disease (IBD) to classify patient disease activity, stratify patients that will benefit from targeted therapies such as anti-TNF, and identify new therapeutic targets. In this study we conducted global transcriptome analysis to identify IBD-related pathways using colon biopsies, which highlighted the coagulation gene pathway as one of the most enriched gene sets in IBD subjects. Using this gene-network analysis across 14 independent cohorts and 1800 intestinal biopsies, we found that amongst the coagulation pathway genes, plasminogen activator inhibitor-1 (PAI-1) expression was highly enriched in active disease and in patients with IBD who did not respond to anti-TNF biologic therapy, and that PAI-1 is a key link between the epithelium and inflammation. Functionally, PAI-1 and its direct target, the fibrinolytic protease tissue plasminogen activator (tPA), played an important role in regulating intestinal inflammation. Intestinal epithelial cells produced tPA, which was protective against chemical and mechanical- mediated colonic injury in mice. In contrast, PAI-1 exacerbated mucosal damage by blocking tPA-mediated cleavage and activation of anti-inflammatory TGF-β, whereas the inhibition of PAI-1 reduced both mucosal damage and inflammation. This study identifies an immune-coagulation gene axis in IBD where elevated PAI-1 may contribute to more aggressive disease.

Inhibition of plasminogen activator inhibitor-1 attenuates against intestinal fibrosis in mice

“…Although the antifibrinolytic PAI-1 functions have received most of the attention in research on tissue fibrosis, 22 more recent report has demonstrated a correlation between enhanced PAI-1 expression and inflammation in IBD patients and murine acute colitis model. 11 In the present study, we ob- served PAI-1 overexpression at active lesions in both patients with CD and mice with the chronic colitis; this overexpression seems to exacerbate intestinal fibrosis and PAI-1 inhibitor is a potential drug candidate for targeted therapy. As PAI-1 inhibition induced MMP-9 activation in the TNBS colitis model, PAI-1-mediated MMP-9 activity inhibition could be a key mechanism via which ECM is deposited in the lesions.…”

“…10 Very recently, it has been reported that PAI-1 expression was highly enriched in active lesions in both patients with IBD and mice with experimental colitis, and confirmed that PAI-1 and its direct target, tPA, played an important role in regulating intestinal inflammation. 11 However, their functions have been only validated in the acute phase of experimetal colitis and its correlation with intestinal fibrogenesis observed in the chronic phase has remained obscure.…”

The role of interleukin-17 in tumor development and progression

“…The impact on mRNA metabolism also enables IL-17 to synergize with other cytokines such as TNF to amplify the inflammatory response (Chiricozzi et al, 2011). Interestingly, IL-17 has been shown to cooperate with a wide range of signaling activators, including IFN-γ, IL-13, TGF-β, and even microbial products (Fabre et al, 2014a;Hall et al, 2017;Kaiko et al, 2019;Teunissen et al, 1998;Verma et al, 2017). Such promiscuity is highly relevant but poorly understood in the context of intratumoral inflammation, which is usually driven by a myriad of factors and exhibits considerable heterogeneity, even among tumors of the same tissue origin.…”

Elastin is a key factor of tumor development in colorectal cancer

“…Statistical significance was set at FDR < 0.05. All target gene expression was calculated as log 2 intensity robust multi-array average signals (Log 2 transformed intensity value) [18,19].…”