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A cell-penetrating peptide suppresses inflammation by inhibiting NF-?B signaling.

ABSTRACT: Nuclear factor-?B (NF-?B) is a central regulator of immune response and a potential target for developing anti-inflammatory agents. Mechanistic studies suggest that compounds that directly inhibit NF-?B DNA binding may block inflammation and the associated tissue damage. Thus, we attempted to discover peptides that could interfere with NF-?B signaling based on a highly conserved DNA-binding domain found in all NF-?B members. One such small peptide, designated as anti-inflammatory peptide-6 (AIP6), was characterized in the current study. AIP6 directly interacted with p65 and displayed an intrinsic cell-penetrating property. This peptide demonstrated significant anti-inflammatory effects in vitro and in vivo. In vitro, AIP6 inhibited the DNA-binding and transcriptional activities of the p65 NF-?B subunit as well as the production of inflammatory mediators in macrophages upon stimulation. Local administration of AIP6 significantly inhibited inflammation induced by zymosan in mice. Collectively, our results suggest that AIP6 is a promising lead peptide for the development of specific NF-?B inhibitors as potential anti-inflammatory agents.

SUBMITTER: Wang YF

PROVIDER: S-EPMC3188757 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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A cell-penetrating peptide suppresses inflammation by inhibiting NF-κB signaling.

Wang Yu Fu YF Xu Xiang X Fan Xia X Zhang Chun C Wei Qiang Q Wang Xi X Guo Wei W Xing Wei W Yu Jian J Yan Jing-Long JL Liang Hua-Ping HP

Molecular therapy : the journal of the American Society of Gene Therapy 20110510 10

Nuclear factor-κB (NF-κB) is a central regulator of immune response and a potential target for developing anti-inflammatory agents. Mechanistic studies suggest that compounds that directly inhibit NF-κB DNA binding may block inflammation and the associated tissue damage. Thus, we attempted to discover peptides that could interfere with NF-κB signaling based on a highly conserved DNA-binding domain found in all NF-κB members. One such small peptide, designated as anti-inflammatory peptide-6 (AIP6 ...[more]

PMID: 21556052

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Project description:ObjectivesBiosurfactants with anti-inflammatory activity may alleviate skin irritation caused by synthetic surfactants in cleaning products. Sophorolipid (SL) is a promising alternative to synthetic surfactants. However, there are few reports on the anti-inflammatory activity of SL and the underlying mechanism. The purpose of this work is to verify that lipopolysaccharide (LPS)-induced inflammation could be inhibited through targeting the pathway of nuclear factor-κB (NF-κB) in RAW264.7 cells.MethodsThe influence of SL on cytokine release was investigated by LPS-induced RAW264.7 cells using ELISA. The quantification of the protein expression of corresponding molecular markers was realized by Western blot analysis. Flow cytometry was employed to determine the levels of Ca2+ and reactive oxygen species (ROS). The relative expression of inducible nitric oxide synthase (INOS) and cyclooxygenase-2 (COX-2) was determined by RT-PCR. An immunofluorescence assay and confocal microscope were used to observe the NF-κB/p65 translocation from the cytoplasm into the nucleus. The likely targets of SL were predicted by molecular docking analysis.ResultsSL showed anti-inflammatory activity and reduced the release of inflammatory cytokines including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and nitric oxide (NO). The experimental results show that SL suppressed the Ca2+ and ROS levels influx in the LPS-induced RAW264.7 cells and alleviated the LPS-induced expression of iNOS and COX-2, the LPS-induced translocation of NF-κB (p65) from the cytoplasm into the nucleus, and the expression of phosphorylated proteins such as p65 and IκBα. Furthermore, molecular docking analysis showed that SL may inhibit inflammatory signaling by competing with LPS to bind TLR4/MD-2 through hydrophobic interactions and by inhibiting IKKβ activation through the hydrogen bonding and hydrophobic interactions.ConclusionThis study demonstrated that SL exerted anti-inflammatory activity via the pathway of NF-κB in RAW264.7 cells.

Project description:Breast cancer metastasis is the primary cause of mortality of patients with breast cancer. The present study aimed to explore the role and underlying mechanisms of IGJ in the invasion and metastasis of breast cancer. The Cancer Genome Atlas database was utilized to analyze the differential gene expression profiles in patients with breast cancer with or without metastasis; the target gene, joining chain of multimeric IgA and IgM (JCHAIN, also known as IGJ, as referred to herein), with significant expression and with prognostic value was screened. The expression levels of IGJ in human breast cancer paired tissues and cell lines were detected using reverse transcription‑quantitative PCR and western blot analysis. IGJ differential expression was detected in paired human breast cancer tissues using immunohistochemistry. The role of IGJ in breast cancer was verified using CCK‑8, invasion and migration assays, and scratch tests in vivo and in vitro. Further exploration of the role and mechanism of IGJ in breast cancer was conducted through Gene Set Enrichment Analysis, Kyoto Encyclopedia of Genes and Genomes analysis, western blot analysis and immunofluorescence experiments. Through the analysis of gene expression profiles, it was found that IGJ was poorly expressed in patients with breast cancer with metastasis compared to patients with non‑metastatic breast cancer. The overexpression of IGJ was associated with an improved distant metastasis‑free survival and overall survival (OS). COX multivariate regression analysis demonstrated that IGJ was an independent prognostic factor for the OS and relapse‑free survival of patients with breast cancer. In comparison to healthy breast cancer adjacent tissues and cell lines, IGJ was poorly expressed in breast cancer tissues and cell lines (P<0.05). Further analyses indicated that the overexpression of IGJ suppressed the proliferation, invasion and metastasis of breast cancer cells in vivo and in vitro by inhibiting the occurrence of epithelial‑to‑mesenchymal transition (EMT) and suppressing the nuclear translocation of p65. Finally, rescue experiments indicated that IGJ restricted the proliferation and metastasis of breast cancer cells by regulating the NF‑κB signaling pathway. On the whole, the present study demonstrates that IGJ suppresses the invasion and metastasis of breast cancer by inhibiting both the occurrence of EMT and the NF‑κB signaling pathway. These findings may provide novel biomarkers and potential therapeutic targets for the treatment of metastatic breast cancer.

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A cell-penetrating peptide suppresses inflammation by inhibiting NF-?B signaling.

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A cell-penetrating peptide suppresses inflammation by inhibiting NF-κB signaling.

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