Eleutherococcus senticosus extract attenuates LPS-induced iNOS expression through the inhibition of Akt and JNK pathways in murine macrophage
Laboratory of Clinical Biology and Pharmacogenomics, College of Oriental Medicine, Kyunghee University, Seoul 130-701, South Korea. Journal of Ethnopharmacology
(Impact Factor: 3).
09/2007; 113(1):183-7. DOI: 10.1016/j.jep.2007.05.023
Eleutherococcus senticosus (Araliaceae) is immunological modulator which has been successfully used for anti-inflammatory effectors on anti-rheumatic diseases in oriental medicine. Mitogen-activated protein kinases (MAPKs) and Akt modulate the transcription of many genes involved in the inflammatory process. In this study, we investigated the inhibitory effects of Eleutherococcus senticosus on the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharides (LPS)-activated macrophages. Finally, we studied the involvement of MAPKs and Akt signaling in the protective effect of Eleutherococcus senticosus in LPS-activated macrophages. Eleutherococcus senticosus significantly attenuated LPS-induced iNOS expression but not COX-2 expression. In using the standard inhibitors (MAPKs and Akt), our results show that Eleutherococcus senticosus downregulates inflammatory iNOS expression by blocking JNK and Akt activation.
Available from: Elena Pomari
- "Eleutherococcus senticosus (ES) is used as an immunological modulator in Oriental medicine.20 It has been used to treat stress-induced physiological changes and various allergic disorders.21–23 "
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Arctium lappa (AL), Camellia sinensis (CS), Echinacea angustifolia, Eleutherococcus senticosus, Panax ginseng (PG), and Vaccinium myrtillus (VM) are plants traditionally used in many herbal formulations for the treatment of various conditions. Although they are well known and already studied for their anti-inflammatory properties, their effects on H2O2-stimulated macrophages are a novel area of study.
Materials and methods
Cell viability was tested after treatment with increasing doses of H2O2 and/or plant extracts at different times of incubation to identify the optimal experimental conditions. The messenger (m)RNA expression of TNFα, COX2, IL1β, NFκB1, NFκB2, NOS2, NFE2L2, and PPARγ was analyzed in macrophages under H2O2 stimulation. The same genes were also quantified after plant extract treatment on cells pre-stimulated with H2O2.
A noncytotoxic dose (200 μM) of H2O2 induced active mRNA expression of COX2, IL1β, NFE2L2, NFκB1, NFκB2, NOS2, and TNFα, while PPARγ was depressed. The expression of all genes tested was significantly (P<0.001) regulated by plant extracts after pre-stimulation with H2O2. COX2 was downregulated by AL, PG, and VM. All extracts depressed IL1β expression, but upregulated NFE2L2. NFκB1, NFκB2, and TNFα were downregulated by AL, CS, PG, and VM. NOS2 was inhibited by CS, PG, and VM. PPARγ was decreased only after treatment with E. angustifolia and E. senticosus.
The results of the present study indicate that the stimulation of H2O2 on RAW267.4 cells induced the transcription of proinflammatory mediators, showing that this could be an applicable system by which to activate macrophages. Plant extracts from AL, CS, PG, and VM possess in vitro anti-inflammatory activity on H2O2-stimulated macrophages by modulating key inflammation mediators. Further in vitro and in vivo investigation into molecular mechanisms modulated by herbal extracts should be undertaken to shed light on the development of novel modulating therapeutic strategies.
Available from: Seyed Mahmoud Hashemi
- "Numerous studies of macrophage function have
shownvarious stimulators such macrophage responses
to specific stimulatorssuch as LPS. These
studies encompass the effects of LPS on genetic
reprogramming and the expression of pro-inflammatory
genes (11, 13), the signal transduction of
LPS/TLR4 (6, 14, 15), inhibitors and stimulators
of LPS function (7, 16-20), and macrophage migratory
and inflammatory response to LPS (10,
21). In spite of that, all studies have done with the
same cells called macrophages, and the same stimulus
called LPS; we see discrepancies in results
that make it difficult to use the same stimulus like
LPS in a correct way for obtaining the favorite result. "
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ABSTRACT: Macrophages influence their environment and surrounding immune cells as soon as stimulators affect them. Different sources of macrophages induce different reactions in their neighboring immune cells,which result in non-uniform immunologic outcomes. In this experimental research, we compare the behavior of peritoneal macrophages to lipopolysaccharide (LPS) stimulation from BALB/cmice as an indicator of a type 2 immune response and from C57BL/6 mice as an indicator of a type 1 immune response.
In this experimental study, peritoneal macrophages prepared from thioglycolate stimulated BALB/c and C57BL/6 micewere treated with 1µg/ml LPS. At different time points after LPS treatment, nitric oxide (NO), interferon gamma (IFN-λ), interleukin 4 (IL-4),transforming growth factor β1(TGF-β1), interleukin 17 (IL-17), and interleukin 10(IL-10) production were measured in the supernatants of all macrophage cultures. Indoleamine 2, 3 dioxygenase (IDO) and phagocytic activitywere analyzed in the different experimental groups. The supernatant effects of LPS-treated macrophages on splenocyte proliferation was assessed by the colorimetric method using a 3-(4,5-Dimethylthiazol- 2-yl)-2, 5-diphenyltetrazolium bromide (MTT) reagent.
According to cytokine analysis, different mouse strains show different cytokine patterns in response to LPS. C57BL/6 macrophages produced more IL-17, IL-10, and IFN-λ, while BALB/c macrophages produced more TGF-β1 and IL-4. There was no significant difference in IDO activity between strains (p≤0.05). BALB/c mice produced more NO inthe first 24 hours after LPS treatment,but C57BL/6 produced more NO at 72 hours post-LPS treatment. Macrophages from both strains hada suppressor effect on splenocyte proliferation, but this effect was stronger in BALB/c mice.
The results show that macrophages from different genetic backgrounds respond differently to the same stimulus in aspects of type, intensity, and time of response. The consideration of these aspects will enableresearchers to use correct treatment programs for immune-regulation or immunotherapy.
Available from: José Maurício Sforcin
- "During inflammatory diseases, macrophages produce an excessive amount of mediators including inflammatory cytokines (Jung et al., 2007). Interleukin (IL)-1b is a pleiotropic pro-inflammatory cytokine inducing systemic and local responses to infection. "
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ABSTRACT: Since propolis and phenolic compounds, such as cinnamic and coumaric acids, have several biological properties, their immunomodulatory effect on cytokine production (IL-1β, IL-6 and IL-10) was investigated. Peritoneal macrophages from BALB/c mice were incubated with propolis, coumaric and cinnamic acids in different concentrations and the concentrations that inhibited cytokine production were tested before or after macrophage challenge with LPS, to evaluate a possible immunomodulatory action. Propolis and the acids stimulated IL-1β production, while IL-6 production was significantly inhibited after incubation with propolis (5, 50 and 100 µg/well), coumaric and cinnamic acids (50 and 100 µg/well). In LPS-challenge protocols, inhibitory concentrations of cinnamic and coumaric acids after LPS incubation prevented efficiently its effects on IL-6 production, whereas propolis inhibited LPS effects both before and after its addition. Propolis, coumaric and cinnamic acids (50 and 100 µg/well) inhibited IL-10 production as well. Both acids showed a similar inhibitory activity on IL-10 production when added after LPS challenge, while propolis counteracted LPS action when added before and after LPS incubation. Propolis modulated the immune/inflammatory response, depending on the concentration. Its efficiency may occur due to the synergistic effect of its compounds, and cinnamic and coumaric acids may be involved in the action of propolis on cytokine production. Copyright © 2012 John Wiley & Sons, Ltd.
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