N-Acetyl-Seryl-Aspartyl-Lysyl-Proline Mitigates Experimental Colitis Through Inhibition of Intestinal Mucosal Inflammatory Responses via MEK-ERK Signaling

Abstract

N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous immunomodulatory peptide that is generated from thymosin b4 (Tb4) through stepwise hydrolysis, involving meprin-a 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 Tb4 and meprin-a 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.

Potential Mechanisms Mediating the Protective Effects ofTricholoma matsutake-Derived Peptides in Mitigating DSS-Induced Colitis

“…Western blotting analysis was performed according to the method described by Mayangsari and Suzuki, with modifications. 22 Colon tissues were homogenized and lysed with RIPA lysis buffer containing 1 mM PMSF on ice for 30 min, and the supernatants were collected after centrifugation at 10 000g for 10 min at 4 °C to obtain total proteins. Nuclear proteins were obtained according to the manufacturer's protocols of the nuclear and cytoplasmic protein extraction kit.…”

Critical Signaling Transduction Pathways and Intestinal Barrier: Implications for Pathophysiology and Therapeutics

“…N-Acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is a kind of tetrapeptide used for the suppression of inflammation and immune responses. It can inhibit the production of proinflammatory factors by decreasing the activity of MEK-ERK signaling [ 136 ].…”

Therapeutic Effect of Prolyl Endopeptidase Inhibitor in High-fat Diet-induced Metabolic Dysfunction-associated Fatty Liver Disease

“… 10 , 13 However, PREP also negatively modulates inflammatory reactions. 11 , 12 , 14 PREP may exhibit anti-inflammatory and antifibrotic effects through N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), which is released from thymosin β4 (Tβ4) by the combined action of meprin α and PREP. 11 Our previous findings suggested a deficiency in endogenous AcSDKP could accelerate liver fibrosis progression in a carbon tetrachloride (CCl 4 )-induced rat model.…”