MMI-0100 Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice through Targeting MK2 Pathway

Abstract

Backgrounds: This study aimed to investigate the protective effects of MMI-0100, a cell-penetrating peptide inhibitor of MAPK-activated protein kinase II (MK2), on acute colitis induced by dextran sodium sulfate (DSS). Mice were injected intraperitoneally with different doses of MMI-0100 (0.5 and 1 mg/kg per day, six days). The physiological indexes, the parameters for colonic pathological injury and the intensity of inflammatory responses were evaluated by histological staining, quantitative PCR, western blotting, and immunostaining. MMI-0100 attenuated DSS-induced body weight loss, colon length shortening, and colonic pathological injury, including decreased myeloperoxidase (MPO) and inhibited inflammatory cell infiltration. MMI-0100 suppressed DSS-induced activation of CD11b+ and F4/80 positive cell, and dramatically decreased the expression of a series of pro-inflammatory cytokines such as TNF-α, IL-6, IL-1β, TGF- β, IFN-γ, IL-17A, COX-2 and iNOS. A TUNEL assay showed that MMI-0100 protected against DSS-induced apoptosis. This is consistent with the results of Western blotting assay in apoptosis-related proteins including Bcl-2, BAX, caspase-3. The anti-inflammatory effects of MMI-0100 on DSS-induced colitis were achieved by down-regulating the phosphorylation level of MK2, IκBα and p65 protein. The current study clearly demonstrates a protective role for MMI-0100 in experimental IBD.

Mangiferin ameliorates cardiac fibrosis in D-galactose-induced aging rats by inhibiting TGF-β/p38/MK2 signaling pathway

“…In our present work, we further identified the abilities of mangiferin on attenuating cardiac oxidative stress, inflammation and fibrosis via inhibiting the activation of TGF-β1/p38/MK2 signaling pathway. MMI-0100 is a cell-penetrating peptide inhibitor of MK2 [ 34 ]. MMI-0100 had exerted anti-cardiac fibrosis ability [ 15 ].…”

MK2 Is Required for Neutrophil-Derived ROS Production and Inflammatory Bowel Disease

“…The oxidative stress also could activate p38 MAPK, JNK, and BMK1 signals (46). MK2 is one of the downstream kinases of p38 MAPK and is activated in the process of IBD (20). It is reported that MK2 regulated neutrophil activation by p38-dependent and ERK-dependent signal pathways (39,48,49).…”

“…Mourey et al (32) reported that MK2 contributed to intestinal inflammation in the progression of IBD. Wang et al reported that MK2 inhibitor could reverse DSS-induced acute colitis by inhibiting the production of a series pro-inflammatory cytokines in the colon and exerted anti-inflammatory effects against inflammatory disease (20,33,34). But the specific relationship between MK2 and IBD was not clear and needs to be further explored.…”

“…MK2 plays an essential role in the progression of inflammation (24,25). Wang et al (20) reported that MK2 inhibitor MMI-0100 could ameliorate DSS-induced colitis in mice through targeting the MK2 pathway. In order to determine the role of myeloid lineage cell MK2 in IBD, we compared pathological changes of DSS-induced IBD in MK2 lyz2−KO mice with those in MK2 lyz2−WT mice.…”

“…MK2, as a pro-inflammatory factor, played a key role in series diseases, such as rheumatoid arthritis (RA), psoriasis, vasculitis, and IBD (18,19). Recently, Wang et al (20) reported that MK2 inhibitor, MMI-0100, could ameliorate dextran sulfate sodium (DSS)-induced colitis in mice, suggesting that MK2 might be a therapeutic target for IBD. However, the specific role of MK2 and its way of action in the pathogenesis of IBD are still unclear and need to be further explored.…”