Abstract
N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous immunomodulatory peptide that is generated from thymosin β4 (Tβ4) through stepwise hydrolysis, involving meprin-α and prolyl endopeptidase (PREP). It is well acknowledged that AcSDKP exerts beneficial effects on multiple cardiovascular and renal diseases. However, the functional role of AcSDKP in inflammatory bowel disease (IBD) remains poorly understood. Here, we aimed to assess the content of AcSDKP in patients with IBD and investigate the impact of AcSDKP on intestinal inflammation in IBD. We found that in the inflamed mucosal specimens of patients with ulcerative colitis, the expression levels of Tβ4 and meprin-α were decreased, while PREP was expressed at similar levels to non-inflamed mucosa. In vitro, AcSDKP inhibited the expression of proinflammatory factors in intestinal epithelial cells partially by reducing the activation of MEK-ERK signaling. In vivo studies showed that transgenic mice, with lower levels of AcSDKP, were more vulnerable to dextran sulfate sodium (DSS)-induced colitis and exhibited more severe intestinal inflammatory responses. On the other hand, exogenous AcSDKP infusion significantly attenuated the clinical symptoms and intestinal mucosal inflammation in DSS-induced mice. In conclusion, results from this study demonstrated the anti-inflammatory function of AcSDKP within the intestine and suggest that AcSDKP has a promising therapeutic potential for IBD treatment.
Highlights
Inflammatory bowel disease (IBD) defines a group of complex disorders, characterized by chronic relapsing inflammation of the gastrointestinal tract, of which ulcerative colitis (UC) and Crohn's disease (CD) are the most typical forms
To determine whether colonic AcSDKP level correlates with inflammation in inflammatory bowel disease (IBD) patients, we first examined the expression of thymosin b4 (Tb4), the precursor of AcSDKP, in paired inflamed and noninflamed biopsy mucosa from A-UC patients
We found that meprin-a mRNA expression was markedly decreased in the inflamed mucosa of A-UC patients compared with the non-inflamed mucosa from the same patients (Figure 1A)
Summary
Inflammatory bowel disease (IBD) defines a group of complex disorders, characterized by chronic relapsing inflammation of the gastrointestinal tract, of which ulcerative colitis (UC) and Crohn's disease (CD) are the most typical forms. The specific pathogenesis of IBD remains unclear, it is well established that the chaotic patterns of cytokine networks, along with the aberrant trafficking of immune cells, play a central role in the inflammatory process of IBD (Friedrich et al, 2019; Neurath, 2019). There are still some limitations with respect to the successful use of these biologic agents in clinical practice. These include the high cost that imposes heavy economic burden on the patients, loss of effectiveness over time, and increased risk of opportunistic infections in the long-term (Danese et al, 2015). It is imperative to search for safer and more efficient agents for IBD therapy, with clearly understood molecular mechanisms
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