Nanostructured, Self-Assembling Peptide K5 Blocks TNF-αand PGE2Production by Suppression of the AP-1/p38 Pathway

Nanostructured, self-assembling peptides hold promise for a variety of regenerative medical applications such as 3D cell culture systems, accelerated wound healing, and nerve repair. The aim of this study was to determine whether the self-assembling peptide K5 can be applied as a carrier of anti-inflammatory drugs. First, we examined whether the K5 self-assembling peptide itself can modulate various cellular inflammatory responses. We found that peptide K5 significantly suppressed the release of tumor-necrosis-factor- (TNF-)αand prostaglandin E2(PGE2) from RAW264.7 cells and peritoneal macrophages stimulated by lipopolysaccharide (LPS). Similarly, there was inhibition of cyclooxygenase- (COX-) 2 mRNA expression assessed by real-time PCR, indicating that the inhibition is at the transcriptional level. In agreement with this finding, peptide K5 suppressed the translocation of the transcription factors activator protein (AP-1) and c-Jun and inhibited upstream inflammatory effectors including mitogen activated protein kinase (MAPK), p38, and mitogen-activated protein kinase kinase 3/6 (MKK 3/6). Whether this peptide exerts its effects via a transmembrane or cytoplasmic receptor is not clear. However, our data strongly suggest that the nanostructured, self-assembling peptide K5 may possess significant anti-inflammatory activity via suppression of the p38/AP-1 pathway.

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Olea europaea Suppresses Inflammation by Targeting TAK1-Mediated MAP Kinase Activation

Molecules ◽

10.3390/molecules26061540 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1540

Author(s):

Chaoran Song ◽

Mi-Yeon Kim ◽

Jae Youl Cho

Keyword(s):

Protein Kinase ◽

Olea Europaea ◽

Inflammatory Responses ◽

Target Protein ◽

Mitogen Activated Protein Kinase ◽

Raw264.7 Cells ◽

Mitogen Activated Protein ◽

Anti Inflammatory ◽

Protein Kinase Kinase ◽

Olea Europaéa

Possessing a variety of medicinal functions, Olea europaea L. is widely cultivated across the world. However, the anti-inflammatory mechanism of Olea europaea is not yet fully elucidated. In this study, how the methanol extract of the leaves of Olea europaea (Oe-ME) can suppress in vitro inflammatory responses was examined in terms of the identification of the target protein. RAW264.7 and HEK293T cells were used to study macrophage-mediated inflammatory responses and to validate the target protein using PCR, immunoblotting, nuclear fraction, overexpression, and cellular thermal shift assay (CETSA) under fixed conditions. Oe-ME treatment inhibited the mRNA expression levels of cyclooxygenase (COX)-2, matrix metallopeptidase (MMP)-9, and intercellular adhesion molecule-1 (ICAM-1) in activated RAW264.7 cells. Oe-ME diminished the activation of activator protein (AP)-1 and the phosphorylation of its upstream signaling cascades, including extracellular signal regulated kinase (ERK), mitogen-activated protein kinase kinase 1/2 (MEK1/2), c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase kinase 3/6 (MKK3/6), p38, MKK7, and transforming growth factor-β-activated kinase 1 (TAK1), in stimulated-RAW264.7 cells. Overexpression and CETSA were carried out to verify that TAK1 is the target of Oe-ME. Our results suggest that the anti-inflammatory effect of Oe-ME could be attributed to its control of posttranslational modification and transcription of TAK1.

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Differential effect of p38 and MK2 kinase inhibitors on the inflammatory and toxicity biomarkers in vitro

Human & Experimental Toxicology ◽

10.1177/0960327117715901 ◽

2017 ◽

Vol 37 (5) ◽

pp. 521-531 ◽

Cited By ~ 2

Author(s):

RK Singh ◽

M Diwan ◽

SG Dastidar ◽

AK Najmi

Keyword(s):

Protein Kinase ◽

Caspase 3 ◽

Kinase Inhibitors ◽

Inflammatory Responses ◽

Interferon Γ ◽

Mitogen Activated Protein Kinase ◽

Toxicity Biomarkers ◽

Mitogen Activated Protein ◽

Anti Inflammatory

Background: Many inflammatory responses including chemotaxis, production of nitric oxide, and modulation of pro-inflammatory cytokines in immunological cells are mediated by p38MAPK. Due to its pivotal role, p38MAPK has been extensively explored as a molecular target for inhibition of chronic inflammation; however, it has not been successful so far due to serious toxicity issues. Among several downstream substrates of p38, mitogen-activated protein kinase-activated protein kinase 2 (MK2) has been reported to be a direct and essential downstream component in regulation of innate immune and inflammatory responses. Thus, in this study, we aimed to understand relative molecular differences between p38 and MK2 kinase inhibition in terms of a comparative anti-inflammatory potential along with molecular regulation of toxicity biomarkers such as Phospho c-Jun N-Terminal Kinase (pJNK), caspase-3, and hepatic enzyme levels in relevant human cells in vitro. Results: Both p38 and MK2 inhibitors attenuated lipopolysaccharide-induced pro-inflammatory biomarkers expression. In addition, both these kinase inhibitors inhibited release of Th1 and Th17 cytokines in phytohemagglutinin-induced cells with MK2 inhibitor showing a better potency for inhibition of Th1 cytokine release, interferon-γ. In the mechanistic differentiation studies, p38 inhibitors displayed an increase in pJNK and caspase-3 activity in U937 cells and elevation in aspartate transaminase enzyme in HepG2 cells, whereas MK2 inhibitor did not show such adverse toxic effects. Conclusion: Taken together, inhibition of MK2 kinase can be a relatively preferred strategy as an anti-inflammatory therapy over direct inhibition of p38 kinase in p38MAPK pathway.

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Natural feed contaminant zearalenone decreases the expressions of important pro- and anti-inflammatory mediators and mitogen-activated protein kinase/NF-κB signalling molecules in pigs

British Journal Of Nutrition ◽

10.1017/s0007114513002675 ◽

2013 ◽

Vol 111 (3) ◽

pp. 452-464 ◽

Cited By ~ 38

Author(s):

Gina Cecilia Pistol ◽

Mihail Alexandru Gras ◽

Daniela Eliza Marin ◽

Florentina Israel-Roming ◽

Mariana Stancu ◽

...

Keyword(s):

Immune Response ◽

Protein Kinase ◽

Matrix Metalloproteinases ◽

Inflammatory Mediators ◽

Interferon Γ ◽

Mitogen Activated Protein Kinase ◽

Economic Point ◽

Mitogen Activated Protein ◽

Anti Inflammatory

Zearalenone (ZEA) is an oestrogenic mycotoxin produced byFusariumspecies, considered to be a risk factor from both public health and agricultural perspectives. In the presentin vivostudy, a feeding trial was conducted to evaluate thein vivoeffect of a ZEA-contaminated diet on immune response in young pigs. The effect of ZEA on pro-inflammatory (TNF-α, IL-8, IL-6, IL-1β and interferon-γ) and anti-inflammatory (IL-10 and IL-4) cytokines and other molecules involved in inflammatory processes (matrix metalloproteinases (MMP)/tissue inhibitors of matrix metalloproteinases (TIMP), nuclear receptors: PPARγ and NF-κB1, mitogen-activated protein kinases (MAPK): mitogen-activated protein kinase kinase kinase 7 (TAK1)/mitogen-activated protein kinase 14 (p38α)/mitogen-activated protein kinase 8 (JNK1)/ mitogen-activated protein kinase 9 (JNK2)) in the liver of piglets was investigated. The present results showed that a concentration of 316 parts per billion ZEA leads to a significant decrease in the levels of pro- and anti-inflammatory cytokines at both gene expression and protein levels, correlated with a decrease in the levels of other inflammatory mediators, MMP and TIMP. The results also showed that dietary ZEA induces a dramatic reduction in the expressions ofNF-κB1andTAK1/p38αMAPK genes in the liver of the experimentally intoxicated piglets, and has no effect on the expression ofPPARγmRNA. The present results suggest that the toxic action of ZEA begins in the upstream of the MAPK signalling pathway by the inhibition of TAK1, a MAPK/NF-κB activator. In conclusion, the present study shows that ZEA alters several important parameters of the hepatic cellular immune response. From an economic point of view, these data suggest that, in pigs, ZEA is not only a powerful oestrogenic mycotoxin but also a potential hepatotoxin when administered through the oral route. Therefore, the present results represent additional data from cellular and molecular levels that could be taken into account in the determination of the regulation limit of the tolerance to ZEA.

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MIP‐1α induces inflammatory responses by upregulating chemokine receptor 1/chemokine receptor 5 and activating c‐Jun N‐terminal kinase and mitogen‐activated protein kinase signaling pathways in acute pancreatitis

Journal of Cellular Biochemistry ◽

10.1002/jcb.27049 ◽

2018 ◽

Vol 120 (3) ◽

pp. 2994-3000

Author(s):

Xingmao Wu ◽

Kaiqiang Ji ◽

Haiyuan Wang ◽

Yang Zhao ◽

Jia Jia ◽

...

Keyword(s):

Acute Pancreatitis ◽

Protein Kinase ◽

Signaling Pathways ◽

Chemokine Receptor ◽

Inflammatory Responses ◽

Mitogen Activated Protein Kinase ◽

Kinase Signaling ◽

Mitogen Activated Protein ◽

Protein Kinase Signaling ◽

Chemokine Receptor 5

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Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway

Nature Medicine ◽

10.1038/74680 ◽

2000 ◽

Vol 6 (4) ◽

pp. 422-428 ◽

Cited By ~ 1471

Author(s):

Leo E. Otterbein ◽

Fritz H. Bach ◽

Jawed Alam ◽

Miguel Soares ◽

Hong Tao Lu ◽

...

Keyword(s):

Carbon Monoxide ◽

Protein Kinase ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

Anti Inflammatory ◽

Kinase Pathway

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Inhibition of Inflammatory Responses by Centella asiatica via Suppression of IRAK1-TAK1 in Mouse Macrophages

The American Journal of Chinese Medicine ◽

10.1142/s0192415x20500548 ◽

2020 ◽

Vol 48 (05) ◽

pp. 1103-1120

Author(s):

Young-Chang Cho ◽

Huong Lan Vuong ◽

Jain Ha ◽

Sewoong Lee ◽

Jiyoung Park ◽

...

Keyword(s):

Transforming Growth Factor ◽

Inflammatory Responses ◽

Centella Asiatica ◽

Prostaglandin E ◽

Methanol Fraction ◽

Raw 264.7 Macrophages ◽

Inflammatory Mechanism ◽

Mouse Macrophages ◽

Mitogen Activated Protein ◽

Anti Inflammatory

Centella asiatica (L.) Urb. (C. asiatica) has been widely treated for inflammation-related diseases in China for thousands of years. While C. asiatica showed relevant effects as traditional medicine, the mechanism of C. asiatica suppressing inflammation has not been thoroughly investigated. Therefore, this study was conducted to reveal the anti-inflammatory mechanism of methanol fraction from C. asiatica (MCA) at the molecular level in murine macrophages. Levels of inflammation-related mediators were observed with treatment of MCA. MCA significantly suppressed nitric oxide production and iNOS expression in RAW 264.7 macrophages. Prostaglandin E2 production was alleviated by MCA via the downregulation of cyclooxygenase-2. MCA treatment also reduced pro-inflammatory tumor necrosis factor-[Formula: see text] and interleukin (IL)-6 levels. LPS/D-GalN-induced acute hepatitis in mouse was alleviated by MCA treatment. In addition, MCA decreased the phosphorylation of inhibitory [Formula: see text]B[Formula: see text] (I[Formula: see text]B[Formula: see text]) at Ser32/36 and thereby blocked I[Formula: see text]B[Formula: see text] degradation. TXY motif phosphorylation in the activation loops of mitogen-activated protein kinases (MAPKs) was also suppressed by MCA treatment. Further investigation revealed that MCA inhibited transforming growth factor-[Formula: see text]-activated kinase 1 (TAK1) phosphorylation and IL-1 receptor-associated kinase (IRAK1) degradation, the upstream kinases activating nuclear factor [Formula: see text]B and MAPKs. Taken together, MCA exhibited anti-inflammatory properties via the downregulation of IRAK1-TAK1 signaling pathways.

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2,8-Decadiene-1,10-Diol Inhibits Lipopolysaccharide-Induced Inflammatory Responses Through Inactivation of Mitogen-Activated Protein Kinase and Nuclear Factor-κB Signaling Pathway

Inflammation ◽

10.1007/s10753-015-0283-1 ◽

2015 ◽

Vol 39 (2) ◽

pp. 583-591 ◽

Cited By ~ 3

Author(s):

Mi-Sun Kim ◽

Eun-Kyung Ahn ◽

Seong Su Hong ◽

Joa Sub Oh

Keyword(s):

Protein Kinase ◽

Signaling Pathway ◽

Inflammatory Responses ◽

Nuclear Factor Κb ◽

Mitogen Activated Protein Kinase ◽

Nuclear Factor ◽

Mitogen Activated Protein

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Glycyrrhizin, the main active compound in liquorice, attenuates pro-inflammatory responses by interfering with membrane-dependent receptor signalling

Biochemical Journal ◽

10.1042/bj20082416 ◽

2009 ◽

Vol 421 (3) ◽

pp. 473-482 ◽

Cited By ~ 65

Author(s):

Bärbel Schröfelbauer ◽

Johanna Raffetseder ◽

Maria Hauner ◽

Andrea Wolkerstorfer ◽

Wolfgang Ernst ◽

...

Keyword(s):

Active Compound ◽

Inflammatory Responses ◽

Nuclear Factor Κb ◽

Mitogen Activated Protein Kinase ◽

Raw 264.7 Cells ◽

Cpg Dna ◽

Cellular Attachment ◽

Mitogen Activated Protein ◽

Anti Inflammatory ◽

Factor Α

The triterpene glycoside glycyrrhizin is the main active compound in liquorice. It is used as a herbal medicine owing to its anticancer, antiviral and anti-inflammatory properties. Its mode of action, however, remains widely unknown. In the present study, we aimed to elucidate the molecular mechanism of glycyrrhizin in attenuating inflammatory responses in macrophages. Using microarray analysis, we found that glycyrrhizin caused a broad block in the induction of pro-inflammatory mediators induced by the TLR (Toll-like receptor) 9 agonist CpG-DNA in RAW 264.7 cells. Furthermore, we found that glycyrrhizin also strongly attenuated inflammatory responses induced by TLR3 and TLR4 ligands. The inhibition was accompanied by decreased activation not only of the NF-κB (nuclear factor κB) pathway but also of the parallel MAPK (mitogen-activated protein kinase) signalling cascade upon stimulation with TLR9 and TLR4 agonists. Further analysis of upstream events revealed that glycyrrhizin treatment decreased cellular attachment and/or uptake of CpG-DNA and strongly impaired TLR4 internalization. Moreover, we found that the anti-inflammatory effects were specific for membrane-dependent receptor-mediated stimuli, as glycyrrhizin was ineffective in blocking Tnfa (tumour necrosis factor α gene) induction upon stimulation with PMA, a receptor- and membrane-independent stimulus. These observations suggest that the broad anti-inflammatory activity of glycyrrhizin is mediated by the interaction with the lipid bilayer, thereby attenuating receptor-mediated signalling.

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Identification of Cdc37 as a Novel Regulator of the Stress-Responsive Mitogen-Activated Protein Kinase

Molecular and Cellular Biology ◽

10.1128/mcb.23.15.5132-5142.2003 ◽

2003 ◽

Vol 23 (15) ◽

pp. 5132-5142 ◽

Cited By ~ 34

Author(s):

Hisashi Tatebe ◽

Kazuhiro Shiozaki

Keyword(s):

Protein Kinase ◽

Protein Kinases ◽

Inflammatory Responses ◽

Cellular Level ◽

Mitogen Activated Protein Kinase ◽

Cellular Survival ◽

Evolutionarily Conserved ◽

Mitogen Activated Protein ◽

Extracellular Stimuli ◽

The Stability

ABSTRACT Eukaryotic cells utilize multiple mitogen-activated protein kinases (MAPKs) to transmit various extracellular stimuli to the nucleus. A subfamily of MAPKs that mediates environmental stress stimuli is also called stress-activated protein kinase (SAPK), which has crucial roles in cellular survival under stress conditions as well as inflammatory responses. Here we report that Cdc37, an evolutionarily conserved kinase-specific chaperone, is a positive regulator of Spc1 SAPK in the fission yeast Schizosaccharomyces pombe. Through a genetic screen, we have identified cdc37 as a mutation that compromises signaling through Spc1 SAPK. The Cdc37 protein physically interacts with Spc1, and the cdc37 mutation affects both the cellular level of the Spc1 protein and stress-induced Spc1 phosphorylation by Wis1 MAPK kinase (MAPKK). Consistently, expression of the stress response genes regulated by the Spc1 pathway is compromised in cdc37 mutant cells. On the other hand, a mutation in Hsp90, which often cooperates with Cdc37 in chaperoning protein kinases, does not affect Spc1 SAPK. These results suggest that Spc1 SAPK is a novel client protein for the Cdc37 chaperone, and the Cdc37 function is important to maintain the stability of the Spc1 protein and to facilitate stress signaling from Wis1 MAPKK to Spc1 SAPK.

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