The immune-stimulating peptide WKYMVm has therapeutic effects against ulcerative colitis

Kim, Sang Doo; Kwon, Soonil; Lee, Sung Kyun; Kook, Minsoo; Lee, Ha Young; Song, Ki-Duk; Lee, Hak-Kyo; Baek, Suk‐Hwan; Park, Chan Bae; Bae, Yoe‐Sik

doi:10.1038/emm.2013.77

Cited by 35 publications

(36 citation statements)

References 34 publications

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“…31,32 Other FPR2 agonists have previously been reported to inhibit osteoclastogenesis. 31,32 Other FPR2 agonists have previously been reported to inhibit osteoclastogenesis.…”

Section: Discussionmentioning

confidence: 99%

The protective effect of WKYMVm peptide on inflammatory osteolysis through regulating NF‐κB and CD9/gp130/STAT3 signalling pathway

Chen

et al. 2019

J Cellular Molecular Medi

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The balance between bone formation and bone resorption is closely related to bone homeostasis. Osteoclasts, originating from the monocyte/macrophage lineage, are the only cell type possessing bone resorption ability. Osteoclast overactivity is thought to be the major reason underlying osteoclast‐related osteolytic problems, such as Paget's disease, aseptic loosening of prostheses and inflammatory osteolysis; therefore, disruption of osteoclastogenesis is considered a crucial treatment option for these issues. WKYMVm, a synthetic peptide, which is a potent FPR2 agonist, exerts an immunoregulatory effect. This peptide inhibits the production of inflammatory cytokines, such as (IL)‐1β and TNF‐α, thus regulating inflammation. However, there are only few reports on the role of WKYMVm and FPR2 in osteoclast cytology. In the current study, we found that WKYMVm negatively regulates RANKL‐ and lipopolysaccharide (LPS)‐induced osteoclast differentiation and maturation in vitro and alleviates LPS‐induced osteolysis in animal models. WKYMVm down‐regulated the expression of osteoclast marker genes and resorption activity. Furthermore, WKYMVm inhibited osteoclastogenesis directly through reducing the phosphorylation of STAT3 and NF‐kB and indirectly through the CD9/gp130/STAT3 pathway. In conclusion, our findings demonstrated the potential medicinal value of WKYMVm for the treatment of inflammatory osteolysis.

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“…31,32 Other FPR2 agonists have previously been reported to inhibit osteoclastogenesis. 31,32 Other FPR2 agonists have previously been reported to inhibit osteoclastogenesis.…”

Section: Discussionmentioning

confidence: 99%

The protective effect of WKYMVm peptide on inflammatory osteolysis through regulating NF‐κB and CD9/gp130/STAT3 signalling pathway

Chen

et al. 2019

J Cellular Molecular Medi

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“…In the DSS-induced colitis model, annexin A1 −/− mice are more susceptible to developing enteritis and recover slowly than wild-type mice when the DSS is withdrawn (Babbin et al, 2008), which suggests that annexin A1 regulates intestinal mucosal injury, inflammation and repair. WKYMVm, a FPR2 synthetic agonist from a random peptide library, reverses decreases in body weight, bleeding score and stool score in DSS-treated mice; these functions are inhibited by WRW4 (Kim et al, 2013). Chemokines and chemokine receptors play a key role in gastrointestinal homeostasis and inflammation (Griffith et al, 2014;Hill and Artis, 2010).…”

Section: Discussionmentioning

confidence: 99%

Identification of FAM3D as a new endogenous chemotaxis agonist for the formyl peptide receptors

Xiang

Liang

et al. 2016

Journal of Cell Science

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The family with sequence similarity 3 (FAM3) gene family is a cytokine-like gene family with four members FAM3A, FAM3B, FAM3C and FAM3D. In this study, we found that FAM3D strongly chemoattracted human peripheral blood neutrophils and monocytes. To identify the FAM3D receptor, we used chemotaxis, receptor internalization, Ca 2+ flux and radioligand-binding assays in FAM3D-stimulated HEK293 cells that transiently expressed formyl peptide receptor (FPR)1 or FPR2 to show that FAM3D was a high affinity ligand of these receptors, both of which were highly expressed on the surface of neutrophils, and monocytes and macrophages. After being injected into the mouse peritoneal cavity, FAM3D chemoattracted CD11b+ Ly6G+ neutrophils in a short time. In response to FAM3D stimulation, phosphorylated ERK1/2 and phosphorylated p38 MAPK family proteins were upregulated in the mouse neutrophils, and this increase was inhibited upon treatment with an inhibitor of FPR1 or FPR2. FAM3D has been reported to be constitutively expressed in the gastrointestinal tract. We found that FAM3D expression increased significantly during colitis induced by dextran sulfate sodium. Taken together, we propose that FAM3D plays a role in gastrointestinal homeostasis and inflammation through its receptors FPR1 and FPR2.

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“…We found higher numbers of C. rodentium translocated from the colon to the spleen in Fpr2 −/− mice, which indicate increased epithelial permeability in the absence of this receptor. Epithelial permeability to dextran has been reversed in DSS treated mice following the administration of an Fpr2 agonist highlighting the importance of Fpr2 in maintaining a stable epithelial barrier [48]. Since FPR2/Fpr2 is also highly expressed by phagocytic cells and is involved in their recruitment to inflamed tissues [49,50] the higher titers of C. rodentium found in the spleen of Fpr2 −/− mice may in part be due to poor immunosurveillance of invading bacteria in extraintestinal tissues early during infection, before any C. rodentium-specific IgG antibodies are produced to support clearance of the pathogens [51].…”

Section: Discussionmentioning

confidence: 98%

Formyl peptide receptor 2 orchestrates mucosal protection againstCitrobacter rodentiuminfection

et al. 2019

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Citrobacter rodentium is an attaching and effacing intestinal murine pathogen which shares similar virulence strategies with the human pathogens enteropathogenic-and enterohemorrhagic Escherichia coli to infect their host. C. rodentium is spontaneously cleared by healthy wild-type (WT) mice whereas mice lacking Muc2 or specific immune regulatory genes demonstrate an impaired ability to combat the pathogen. Here we demonstrate that apical formyl peptide receptor 2 (Fpr2) expression increases in colonic epithelial cells during C. rodentium infection. Using a conventional inoculum dose of C. rodentium, both WT and Fpr2 −/− mice were infected and displayed similar signs of disease, although Fpr2 −/− mice recovered more slowly than WT mice. However, Fpr2 −/− mice exhibited increased susceptibility to C. rodentium colonization in response to low dose infection: 100% of the Fpr2 −/− and 30% of the WT mice became colonized and Fpr2 −/− mice developed more severe colitis and more C. rodentium were in contact with the colonic epithelial cells. In line with the larger amount of C. rodentium detected in the spleen in Fpr2 −/− mice, more C. rodentium and enteropathogenic Escherichia coli translocated across an in vitro mucosal surface to the basolateral compartment following FPR2 inhibitor treatment. Fpr2 −/− mice also lacked the striated inner mucus layer that was present in WT mice. Fpr2 −/− mice had decreased mucus production and different mucin O-glycosylation in the colon compared to WT mice, which may contribute to their defect inner mucus layer. Thus, Fpr2 contributes to protection against infection and influence mucus production, secretion and organization.

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The immune-stimulating peptide WKYMVm has therapeutic effects against ulcerative colitis

Cited by 35 publications

References 34 publications

The protective effect of WKYMVm peptide on inflammatory osteolysis through regulating NF‐κB and CD9/gp130/STAT3 signalling pathway

The protective effect of WKYMVm peptide on inflammatory osteolysis through regulating NF‐κB and CD9/gp130/STAT3 signalling pathway

Identification of FAM3D as a new endogenous chemotaxis agonist for the formyl peptide receptors

Formyl peptide receptor 2 orchestrates mucosal protection againstCitrobacter rodentiuminfection

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