Rosiglitazone alleviates lipopolysaccharide‑induced inflammation in RAW264.7 cells via inhibition of NF‑κB and in a PPARγ‑dependent manner
- Authors:
- Published online on: May 11, 2021 https://doi.org/10.3892/etm.2021.10175
- Article Number: 743
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Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Inflammation is a complex pathological response caused by harmful stimuli to the internal and external environment (1). In vitro inflammatory models are typically established by lipopolysaccharide (LPS) or interferon-γ induction in macrophages. Macrophages, which are central cells that produce inflammatory mediators and modulate inflammatory responses in vivo, can be immunomodulated by the secretion of various cytokines or lysosome release (2,3).
The RAW264.7 cell line is derived from mouse mononuclear macrophage leukemia cells (4). RAW264.7 cells are widely used to evaluate the immunomodulatory effects of mononuclear macrophages on nitric oxide (NO) secretion and associated inflammatory signaling pathways (5). LPS stimulates cells to secrete a variety of inflammatory mediators, including nitric oxide (NO), tumor necrosis factor (TNF)-α and interleukin (IL)-1β, via binding to the corresponding receptors on the cell membrane to regulate immune response (6).
NO is the major mediator of oxidative stress, which exacerbates inflammatory responses. Therefore, NO levels are closely associated with the pathogenesis of numerous inflammatory diseases (7). Inducible NO synthase (iNOS) is a vital indicator of the inflammatory response (8). At present, the regulation of NO synthesis and iNOS expression is considered to be a novel therapeutic strategy for inflammatory diseases. Proinflammatory cytokines, including TNF-α, IL-1β and IL-6, can interact with the anti-inflammatory cytokine IL-10 to participate in inflammation regulation (9).
LPS is a major component of the cell wall of Gram-negative bacteria; identification and signal transduction of LPS is an essential step in the self-defense response of the body (10). Previous studies have reported that LPS can promote the development of acute kidney injury by inducing the production of proinflammatory cytokines, including TNF-α, IL-6 and IL-1β (11,12). LPS induction in tyrosine hydroxylase immunoreactive cells selectively inhibit cell viability and increases the culture medium contents of IL-1β, TNF-α and NO (13). Toll-like receptor (TLR)-4 mediates LPS-induced inflammatory responsesin human coronary artery endothelial cells (13). Moreover, LPS can induce inflammatory effects by regulating the nuclear factor (NF)-κB signaling pathway in A549 cells (14). The primary downstream signaling pathways involved in LPS-induced inflammatory responses include the NF-κB, MAPK and JAK-STAT signaling pathways. Activation of the aforementioned signaling pathways further regulates a variety of inflammatory mediators (15).
Previous studies have reported that LPS-induced production of proinflammatory cytokines is associated with the NF-κB signaling pathway (16-19). It is considered to be the central step in LPS-induced macrophage inflammation that exerts a crucial role in promoting iNOS and proinflammatory cytokine expression (20). LPS activates TLR-4 and binds to heat shock protein 60 via activating the NF-κB signaling pathway (21). LPS also induces the production of proinflammatory cytokines by macrophages, thus leading to myocardial hypertrophy and ischemia (22).
LPS-induced inflammation is also associated with peroxisome proliferator-activated receptors (PPARs). PPARγ belongs to the nuclear hormone receptor superfamily and is a ligand-activated transcription factor. PPARγ regulates cell proliferation, differentiation, carbohydrate lipid metabolism and inflammatory responses. PPARs can be divided into three types: PPARα, PPARβ and PPARγ, among which PPARγ is primarily distributed in adipose tissue and the immune system, suggesting its role in fat metabolism and body immunity (23).
Recent studies have demonstrated that PPARγ activation downregulates the expression of NOS, matrix metalloproteinases and adhesion molecules in the mononuclear phagocyte cell line, thereby inhibiting the inflammatory response (24-26). PPARγ agonists are capable of inhibiting the production of proinflammatory cytokines in mononuclear macrophages (23). Pretreatment with a PPARγ ligand can significantly decrease the expression of proinflammatory cytokines in tissues, and alleviate tissue damage at local and distant sites of inflammation (27). PPARγ agonist ligands are split into two major classes, natural ligands and synthetic ligands. Natural ligands are primarily 15-deoxy prostaglandin J2 (15d-PGJ2) and linoleic acid oxidation products, whereas synthetic ligands are primarily thiazolidinedione (TZDs), including pioglitazone, troglitazone and rosiglitazone. Rosiglitazone is the most commonly used drug with the highest bioavailability, strongest drug effect and fewest side effects (28). Previous studies have demonstrated the anti-inflammatory effects of rosiglitazone in diverse models (29). Rosiglitazone upregulatesheme oxygenase-1 expression via the reactive oxygen species-dependent nuclear factor, erythroid 2 like 2-antioxidant response elements axis (30).
Moreover, rosiglitazone could also impair colonic inflammation in mice with experimental colitis (31). However, the mechanism underlying the anti-inflammatory effects of rosiglitazone is not completely understood.
The present study aimed to explore the role of the PPARγ agonist rosiglitazone in the regulation of LPS-induced inflammatory responses and decreases in viability in RAW264.7 cells, as well as its potential underlying mechanisms.
Materials and methods
Cell culture
The RAW264.7 cell line is a mouse mononuclear macrophage leukemia cell line that was obtained from the American Type Culture Collection. Cells were cultured in DMEM (Gibco; Thermo Fisher Scientific, Inc.) supplemented with 10% FBS (Gibco; Thermo Fisher Scientific, Inc.), 100 U/ml penicillin and 100 µg/ml streptomycin in a 5% CO2 incubator at 37˚C. Culture medium was replaced every 2 days.
MTT assay
RAW264.7 cells at the logarithmic growth phase were digested with PBS supplemented with 0.25% EDTA and prepared for cell suspension. After the cell density was adjusted to 2x105/ml, 100 µl cell suspension was added to each well of a 96-well plate. RAW264.7 cells were treated with 100 ng/ml LPS (Sigma-Aldrich; Merck KGaA; L4391), or 1, 2, 5, 10 or 20 µM rosiglitazone (Sigma-Aldrich; Merck KGaA; cat. no. R2408) for 48 or 72 h at 37˚C. Each group consisted of three replicates. Subsequently, cells were incubated with 200 µl 0.5% MTT solution (0.5 mg/ml) for 4 h. The purple formazan was dissolved with DMSO solution. Absorbance was measured at a wavelength of 490 nm using a microplate reader (Bio-Rad Laboratories, Inc.).
Enzyme-linked immunosorbent assay (ELISA)
RAW264.7 cells in the logarithmic growth phase were seeded (1x104/ml; 100 µl/well) into 96-well plates. Following culture for 24 h, cells were pretreated with rosiglitazone at different concentration for 1 h and then treated with LPS for 24 h. Subsequently, the culture medium was collected and cytokine levels were detected using an IL-6 (cat. no. M6000B) and TNFα (cat. no. MTA00B) ELISA kit (R&D Systems, Inc.) according to the manufacturer's protocol.
RNA extraction and reverse transcription-quantitative PCR (RT-qPCR)
Total RNA was extracted from cells using TRIzol® (Thermo Fisher Scientific, Inc.). The RNA concentration of each sample was detected using a NanoDrop 2000 spectrophotometer (Thermo Fisher Scientific, Inc.). Total RNA was reverse transcribed into cDNA using a first-strand cDNA synthesis kit (Takara Bio, Inc.) at 42˚C for 30 min. Subsequently, qPCR was performed for 40 cycles using Hieff™ qPCR SYBR®-Green Master Mix (with ROX; Yeasen Technology, Inc.). The sequences of the primers used for qPCR are presented in Table I. The 2-ΔΔCq method was used for quantitative analysis (32).
Western blotting
Total protein was extracted from cells using RIPA solution (cat. no. 89900; Thermo Fisher Scientific, Inc.). The BCA method was used to determine the protein concentration. A total of 20 µg protein was separated via 10% SDS-PAGE gel and transferred to PVDF membranes. Following blocking with 5% skimmed milk at room temperature for 1 h, the membranes were incubated overnight at 4˚C with primary antibodies (1:1,000 dilution). Subsequently, the membranes were incubated with a HRP-conjugated anti-mouse (1:5,000; cat. no. #7076; Cell Signaling Technology, Inc.) or HRP-conjugated anti-rabbit IgG (1:5,000; cat. no. #7074; Cell Signaling Technology, Inc.) at room temperature for 1 h. p65 (cat. no. 66535-1-Ig), IkB-α (cat. no. 10268-1-AP), PPAR (cat. no. 16643-1-AP) and β-actin (cat. no. 60008-1-Ig) primary antibodies were purchased from ProteinTech Group, Inc. Thephosphorylated (p)-p65 (cat. no. 3033) primary antibody was purchased from Cell Signaling Technology, Inc. Protein bands were visualized using an ECL system with an ImageQuant LAS 500 imager (GE Healthcare). The protein bands were quantified by ImageQuant TL version 8.0 (GE Healthcare).
Cell transfection
Small interfering RNA (si)-PPARγ-1, si-PPARγ-2 and si-negative control were purchased from Shanghai GenePharma Co., Ltd. Briefly, 0.8 µg si RNA or 3 µl Viromer blue transfection reagent (Lipocalyx GmbH) were diluted in 350 µl buffer blue, mixed and stored at room temperature for 15 min. Subsequently, cells were seeded at 1x105 cells/well in a six-well plate and then were incubated with the reagent mixture for 48 h. Culture medium was replaced every 2 days. The siRNA sequences were as follows: si-PPARγ-1: 5'-CCGGGCTCCACACTATGAAGACATTCTCGAGAATGTCTTCATAGTGTGGAGCTTTTT-3'; si-PPARγ-2: 5'-CCGGGCCTCCCTGATGAATAAAGATCTCGAGATCTTTATTCAGGGAGGCTTTTT-3'.
Determination of NO secretion
NO secretion levels were determined using the Griess reagent system kit (Beyotime Institute of Biotechnology). Cells were seeded (1x104/ml) into 96-well plates and incubated for 24 h. Following different treatments for 24 h, 50 µl cell supernatant was collected and plated into 96-well plates at room temperature. Subsequently, 50 µl Griess I and Griess II reagent were added in order at room temperature. Absorbance was measured at a wavelength of 540 nm with microplate reader.
Dual-luciferase reporter gene assay
A total of 2x104 cells were co-transfected with 1 µg mass luciferase-coupled reporter gene for NF-κB and 1 µg Renilla luciferase reporter (Beyotime Institute of Biotechnology) using Viromer blue transfection reagent (High-Tech Gründerfonds). At 48 h post-transfection, cells were pre-treated with rosiglitazone for 1 h and then treated with LPS for 5 h at 37˚C. Following washes with cold PBS, cells were lysed with luciferase lysis buffer (Beyotime Institute of Biotechnology) and luciferase activities were measured using the Dual Luciferase Assay System and a Victor luminometer (Promega Corporation) according to the manufacturer's instructions. Relative NF-κB luciferase activity was normalized to Renilla activity.
Statistical analysis
Statistical analyses were performed using GraphPad software (version 7; GraphPad Software, Inc.). Data are presented as the mean ± SD. Comparisons between groups were analyzed using Kruskal-Wallis test and Dunn's post hoc test. P<0.05 was considered to indicate a statistically significant difference. All experiments were performed three times.
Results
Rosiglitazone reverses LPS-induced decrease in cell viability
Rosiglitazone is an insulin sensitizer and is commonly used for the treatment of type 2 diabetes (33). In order to explore the effect of different concentrations of rosiglitazone on LPS-induced decrease in cell viability, RAW264.7 cells were treated with 1, 2, 5, 10 or 20 µM rosiglitazone to detect the cell cytotoxicity of rosiglitazone. Following treatment for 48 h, cell viability was measured using the MTT assay. Compared with the control group, 1-20 µM rosiglitazone showed no obvious cytotoxic effect on RAW264.7 cells (Fig. 1A). Therefore, 1, 5, 10 and 20 µM rosiglitazone were selected as the extremely low-, low-, middle- and high-dose rosiglitazone groups, respectively. Subsequently, RAW264.7 cells were treated with 100 ng/ml LPS for 48 h. LPS treatment decreased RAW264.7 cell viability compared with the control group. However, middle- and high-dose rosiglitazone treatment for 48 h reversed LPS-induced decrease in cell viability (Fig. 1B); similar results were observed following treatment for 72 h (Fig. 1C).
Effect of rosiglitazone on LPS-induced proinflammatory and anti-inflammatory cytokine expression
In order to explore the effect of rosiglitazone on LPS-induced alterations to the expression of proinflammatory and anti-inflammatory cytokines, mRNA expression levels of IL-1β, TNF-α and IL-10 were detected via RT-qPCR. The results demonstrated that treatment with 100 ng/ml LPS for 48 h remarkably upregulated IL-1β, TNF-α and IL-10 mRNA expression levels. Compared with the LPS group, rosiglitazone treatment downregulated IL-1β, IL-10 and TNF-α mRNA expression levels in a dose-dependent manner (Fig. 2A-C). In order to further verify the aforementioned results, IL-6 and TNF-α contents in the culture medium of different groups were assessed. The ELISA results demonstrated that IL-6 and TNF-α contents in the culture medium of the LPS group were remarkably elevated. However, IL-6 and TNF-α contents were downregulated in the middle- and high-dose groups in a dose-dependent manner (Fig. 2D and E). NO and iNOS mRNA expression levels in RAW264.7 cells, following exposure to LPS and different concentrations of rosiglitazone, were also detected. The results demonstrated that different concentrations of rosiglitazone treatment decreased NO secretion in a dose-dependent manner (Fig. 2F). Similar results were obtained for the detection of iNOS mRNA expression levels via RT-qPCR (Fig. 2G).
Rosiglitazone inhibits the NF-κB signaling pathway in LPS-treated RAW264.7 cells
It has been reported that the NF-κB signaling pathway is greatly involved in inflammatory responses (34). Therefore, whether rosiglitazone could regulate RAW264.7 cell inflammation via the NF-κB signaling pathway was investigated. The activity of the NF-κB-driven luciferase reporter gene was markedly elevated after LPS induction for 48 h. However, middle- and high-dose rosiglitazone treatment inhibited the activity of the NF-κB-driven luciferase reporter gene (Fig. 3A). Moreover, the phosphorylation level of p65 was gradually decreased and IκBα expression was increased with increasing concentrations of rosiglitazone (Fig. 3B and C), indicating that the NF-κB signaling pathway was inhibited by rosiglitazone in a concentration-dependent manner.
PPARγ knockdown impairs the anti-inflammatory effect of rosiglitazone on RAW264.7 cells
In order to verify whether the effect of rosiglitazone on inflammation regulation was mediated via PPARγ, si-PPARγ-RAW264.7 cell lines were constructed. The transfection efficacy of si-PPARγ was verified via western blotting (Fig. 4A). The results indicated that PPARγ knockdown upregulated IL-1β and TNF-α mRNA expression levels (Fig. 4B and C). Similarly, PPARγ knockdown reversed rosiglitazone-induced decrease in p65 phosphorylation levels and increased IκBα expression (Fig. 4D-F).
Discussion
As innate immune cells, macrophages trigger inflammatory and immune responses for self-defense. LPS is a potent inducer of monocyte and macrophage immune responses. When activated by LPS, macrophages release a variety of proinflammatory cytokines and anti-inflammatory cytokines (35). Excessive release of cytokines may lead to extensive tissue damage and pathological alterations (36). Macrophages produce a number of inflammatory mediators, including IL-1β, IL-6, TNF-α and NO (37). LPS induction stimulates the secretion of proinflammatory mediators by macrophages, eventually leading to cell injury and even cell death (38). Therefore, the present study used LPS as an in vitro model of inflammation.
PPARγ is a type of ligand-dependent transcription factor that regulates the proliferation, invasion, differentiation and apoptosis of various cells at the transcriptional level. PPARγ serves a crucial role in various inflammatory injury processes (39-40). Rosiglitazone is a synthetic PPARγ agonist and is widely used for the treatment of type 2 diabetes (41). Previous studies have demonstrated that rosiglitazone serves a neuroprotective role via anti-inflammatory and antioxidant mechanisms after brain trauma (41-43). In the present study, 1-20 µM rosiglitazone showed no obvious cytotoxic effect on RAW264.7 cells. However, rosiglitazone reversed the inhibitory effect of LPS on cell viability, potentially via inhibiting cytokine expression. Moreover, rosiglitazone inhibited LPS-induced proinflammatory cytokine and enzyme expression, including IL-1β, TNF-α, IL-6 and iNOS in RAW264.7 cells. Interestingly, LPS also elevated the expression of IL-10, an anti-inflammatory cytokine, potentially to overcome the proinflammatory cytokines, which is a phenomenon derived from cell self-protective mechanisms (44). Rosiglitazone not only inhibited proinflammatory cytokines, but also repressed anti-inflammatory cytokines, suggesting that it might serve a vital role in balancing the process of inflammation.
To confirm whether the anti-inflammatory effect of rosiglitazone was mediated via PPARγ, si-PPARγ-RAW264.7 cells were constructed. The results indicated that PPARγ knockdown attenuated the inhibitory effect of rosiglitazone on proinflammatory cytokines. Therefore, the aforementioned results suggested that rosiglitazone regulated inflammation via PPARγ activation.
NF-κB is an important transcription factor that regulates the expression of immune and inflammatory response factors (45). Previous studies have demonstrated that the PPARγ/NF-κB signaling pathway is involved in the dynamic balance of the inflammatory response (46-48). Besides, PPARγ agonists, including rosiglitazone, were reported to inhibit the activity of the NF-κB signaling pathway in osteoclastogenesis. The aforementioned studies suggested that PPARγ could partly regulate the level of the NF-κB signaling pathway. NF-κB signaling pathway activation may be the control point for the expression of abundant inflammatory response genes (49). In the present study, rosiglitazone inhibited NF-κBp65 phosphorylation and increased IKBα expression, reversing LPS-induced activation of NF-κB. PPARγ knockdown impaired the effect of rosiglitazone on NF-κB activation. Therefore, the results suggested that the PPARγ/NF-κB signaling pathway might serve as a crucial target for controlling inflammatory responses.
NF-κB is a transcription factor family that regulates a number of genes that are involved in several physiological and pathological processes. In the canonical pathway, NF-κB dimers and molecules of IκB family form a stable complex which prevent dimers translocating to the nucleus. When stimulated by extracellular stimuli, IκB kinase (IKK) is phosphorylated causing the dimers to translocate to the nucleus and activate downstream gene expression (50). Due to the limitation of funding, p-IKKβ as well as the translocation of cytosolic p65 to the nucleus, and other signaling such as MAPK substances were not detected. The effect of IL-1β, TNF-α, IL-6 on NF-κB transcriptional activity were not studied.
In conclusion, the present study demonstrated that rosiglitazone significantly inhibited the LPS-induced inflammatory response in RAW264.7 cells and improved cell viability. Rosiglitazone inhibited the expression level of proinflammatory cytokines, potentially via activating PPARγ and inhibiting NF-κB. The results of the present study provided an experimental basis for the new application of old drugs.
Acknowledgements
The authors would like to thank Dr Changsheng Yan (School of Medical, Xiamen University, Xiamen, China) who offered some suggestions and help with the experiment design.
Funding
Funding: Funding was received from Health and Family Planning Commission (grant no. 2014-2-72), the Natural Science Foundation of Fujian Province (grant no. 2015J01534) and the National Natural Science Foundation of China (grant no. 81702428).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
JPZ and XNY contributed to the study design. YQH, LGC and JJL contributed to the interpretation of data. FZ performed the experiments and YS was responsible for statistical analysis. All authors read and approved the final manuscript. JPS and XNY confirm the authenticity of all the raw data.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
References
|
Chen L, Shen X, Chen G, Cao X and Yang J: Effect of Three-spot seahorse petroleum ether extract on lipopolysaccharide induced macrophage RAW264.7 inflammatory cytokine nitric oxide and composition analysis. J Oleo Sci. 64:933–942. 2015.PubMed/NCBI View Article : Google Scholar | |
|
Dong D, Zhou NN, Liu RX, Xiong JW, Pan H, Sun SQ, Ma L and Wang R: Sarsasapogenin-AA13 inhibits LPS-induced inflammatory responses in macrophage cells in vitro and relieves dimethylbenzene-induced ear edema in mice. Acta Pharmacol Sin. 38:699–709. 2017.PubMed/NCBI View Article : Google Scholar | |
|
Ti D, Hao H, Tong C, Liu J, Dong L, Zheng J, Zhao Y, Liu H, Fu X and Han W: LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b. J Transl Med. 13(308)2015.PubMed/NCBI View Article : Google Scholar | |
|
Schmidt HH, Warner TD, Nakane M, Förstermann U and Murad F: Regulation and subcellular location of nitrogen oxide synthases in RAW264.7 macrophages. Mol Pharmacol. 41:615–624. 1992.PubMed/NCBI | |
|
Tian LX, Tang X, Zhu JY, Zhang W, Tang WQ, Yan J, Xu X and Liang HP: Corrigendum to ‘Cytochrome P450 1A1 enhances Arginase-1 expression, which reduces LPS-induced mouse peritonitis by targeting JAK1/STAT6’ [Cell. Immunol 349 (2020) 104047]. Cell Immunol. 351(104084)2020.PubMed/NCBI View Article : Google Scholar | |
|
Araya AV, Pavez V, Perez C, Gonzalez F, Columbo A, Aguirre A, Schiattino I and Aguillón JC: Ex vivo lipopolysaccharide (LPS)-induced TNF-alpha, IL-1beta, IL-6 and PGE2 secretion in whole blood from type 1 diabetes mellitus patients with or without aggressive periodontitis. Eur Cytokine Netw. 14:128–133. 2003.PubMed/NCBI | |
|
Chiang SS, Chen LS and Chu CY: Active food ingredients production from cold pressed processing residues of Camellia oleifera and Camellia sinensis seeds for regulation of blood pressure and vascular function. Chemosphere. 267(129267)2020.PubMed/NCBI View Article : Google Scholar | |
|
Kim YJ, Hwang SY, Oh ES, Oh S and Han IO: IL-1beta, an immediate early protein secreted by activated microglia, induces iNOS/NO in C6 astrocytoma cells through p38 MAPK and NF-kappaB pathways. J Neurosci Res. 84:1037–1046. 2006.PubMed/NCBI View Article : Google Scholar | |
|
Nie Z, Xia X, Zhao Y, Zhang S, Zhang Y and Wang J: JNK selective inhibitor, IQ-1S, protects the mice against lipopolysaccharides-induced sepsis. Bioorg Med Chem. 30(115945)2020.PubMed/NCBI View Article : Google Scholar | |
|
Lamping N, Dettmer R, Schröder NW, Pfeil D, Hallatschek W, Burger R and Schumann RR: LPS-binding protein protects mice from septic shock caused by LPS or gram-negative bacteria. J Clin Invest. 101:2065–2071. 1998.PubMed/NCBI View Article : Google Scholar | |
|
Shi M, Zeng X, Guo F, Huang R, Feng Y, Ma L, Zhou L and Fu P: Anti-inflammatory pyranochalcone derivative attenuates LPS-induced acute kidney injury via inhibiting TLR4/NF-κB pathway. Molecules. 22(1683)2017.PubMed/NCBI View Article : Google Scholar | |
|
Hou C, Mei Q, Song X, Bao Q, Li X, Wang D and Shen Y: Mono-macrophage-derived MANF protects against lipopolysaccharide-induced acute kidney injury via inhibiting inflammation and renal M1 macrophages. Inflammation. 44:693–703. 2020.PubMed/NCBI View Article : Google Scholar | |
|
Gayle DA, Ling Z, Tong C, Landers T, Lipton JW and Carvey PM: Lipopolysaccharide (LPS)-induced dopamine cell loss in culture: Roles of tumor necrosis factor-alpha, interleukin-1beta, and nitric oxide. Brain Res Dev Brain Res. 133:27–35. 2002.PubMed/NCBI View Article : Google Scholar | |
|
Feng T, Yunfeng N, Jinbo Z, Zhipei Z, Huizhong Z, Li L, Tao J and Yunjie W: Single immunoglobulin IL-1 receptor-related protein attenuates the lipopolysaccharide-induced inflammatory response in A549 cells. Chem Biol Interact. 183:442–449. 2010.PubMed/NCBI View Article : Google Scholar | |
|
Wang J, Pan Y, Cao Y, Zhou W and Lu J: Salidroside regulates the expressions of IL-6 and defensins in LPS-activated intestinal epithelial cells through NF-κB/MAPK and STAT3 pathways. Iran J Basic Med Sci. 22:31–37. 2019.PubMed/NCBI View Article : Google Scholar | |
|
Pan MH, Lin-Shiau SY and Lin JK: Comparative studies on the suppression of nitric oxide synthase by curcumin and its hydrogenated metabolites through down-regulation of IkappaB kinase and NFkappaB activation in macrophages. Biochem Pharmacol. 60:1665–1676. 2000.PubMed/NCBI View Article : Google Scholar | |
|
Karin M and Ben-Neriah Y: Phosphorylation meets ubiquitination: The control of NF-[kappa]B activity. Annu Rev Immunol. 18:621–623. 2000.PubMed/NCBI View Article : Google Scholar | |
|
Chow JC, Young DW, Golenbock DT, Christ WJ and Gusovsky F: Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J Biol Chem. 274:10689–10692. 1999.PubMed/NCBI View Article : Google Scholar | |
|
Faure E, Equils O, Sieling PA, Thomas L, Zhang FX, Kirschning CJ, Polentarutti N, Muzio M and Arditi M: Bacterial lipopolysaccharide activates NF-kappaB through toll-like receptor 4 (TLR-4) in cultured human dermal endothelial cells. Differential expression of TLR-4 and TLR-2 in endothelial cells. J Biol Chem. 275:11058–11063. 2000.PubMed/NCBI View Article : Google Scholar | |
|
Zhang G and Ghosh S: Molecular mechanisms of NF-kappaB activation induced by bacterial lipopolysaccharide through Toll-like receptors. J Endotoxin Res. 6:453–457. 2000.PubMed/NCBI View Article : Google Scholar | |
|
Li X, Huang R, Liu K, Li M, Luo H, Cui L, Huang L and Luo L: Fucoxanthin attenuates LPS-induced acute lung injury via inhibition of the TLR4/MYD88 signaling axis. Aging (Albany NY). 12:2655–2667. 2020.PubMed/NCBI View Article : Google Scholar | |
|
Hernesniemi J, Lehtimäki T, Rontu R, Islam MS, Eklund C, Mikkelsson J, Ilveskoski E, Kajander O, Goebeler S, Viiri LE, Hurme M and Karhunen PJ: Toll-like receptor 4 polymorphism is associated with coronary stenosis but not with the occurrence of acute or old myocardial infarctions. Scand J Clin Lab Invest. 66:667–675. 2006.PubMed/NCBI View Article : Google Scholar | |
|
Wagner KD and Wagner N: PPARs and myocardial infarction. Int J Mol Sci. 21(9436)2020.PubMed/NCBI View Article : Google Scholar | |
|
Daynes RA and Jones DC: Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol. 2:748–759. 2002.PubMed/NCBI View Article : Google Scholar | |
|
Ricote M, Li AC, Willson TM, Kelly CJ and Glass CK: The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 391:79–82. 1998.PubMed/NCBI View Article : Google Scholar | |
|
Jiang C, Ting AT and Seed B: PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 391:82–86. 1998.PubMed/NCBI View Article : Google Scholar | |
|
Azuma Y, Shinohara M, Wang PL and Ohura K: 15-Deoxy-delta(12,14)-prostaglandin J(2) inhibits IL-10 and IL-12 production by macrophages. Biochem Biophys Res Commun. 283:344–346. 2001.PubMed/NCBI View Article : Google Scholar | |
|
Ayza MA, Zewdie KA, Tesfaye BA, Gebrekirstos ST and Berhe DF: Anti-diabetic effect of telmisartan through its partial PPARγ-agonistic activity. Diabetes Metab Syndr Obes. 13:3627–3635. 2020.PubMed/NCBI View Article : Google Scholar | |
|
Paschoal VA, Walenta E, Talukdar S, Pessentheiner AR, Osborn O, Hah N, Chi TJ, Tye GL, Armando AM, Evans RM, et al: Positive reinforcing mechanisms between GPR120 and PPARγ modulate insulin sensitivity. Cell Metab. 31:1173–1188.e5. 2020.PubMed/NCBI View Article : Google Scholar | |
|
Cho RL, Yang CC, Tseng HC, Hsiao LD, Lin CC and Yang CM: Haem oxygenase-1 up-regulation by rosiglitazone via ROS-dependent Nrf2-antioxidant response elements axis or PPARγ attenuates LPS-mediated lung inflammation. Br J Pharmacol. 175:3928–3946. 2018.PubMed/NCBI View Article : Google Scholar | |
|
Celinski K, Dworzanski T, Fornal R, Korolczuk A, Madro A, Brzozowski T and Slomka M: Comparison of anti-inflammatory properties of peroxisome proliferator-activated receptor gamma agonists rosiglitazone and troglitazone in prophylactic treatment of experimental colitis. J Physiol Pharmacol. 64:587–595. 2013.PubMed/NCBI | |
|
Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2000.PubMed/NCBI View Article : Google Scholar | |
|
Akimoto H, Negishi A, Oshima S, Wakiyama H, Okita M, Horii N, Inoue N, Ohshima S and Kobayashi D: Antidiabetic drugs for the risk of alzheimer disease in patients with type 2 DM using FAERS. Am J Alzheimers Dis Other Demen. 35(1533317519899546)2020.PubMed/NCBI View Article : Google Scholar | |
|
Wu Y, Xiao W, Pei C, Wang M, Wang X, Huang D, Wang F and Wang Z: Astragaloside IV alleviates PM2.5-induced lung injury in rats by modulating TLR4/MyD88/NF-κB signalling pathway. Int Immunopharmacol. 91(107290)2020.PubMed/NCBI View Article : Google Scholar | |
|
Islam SU, Lee JH, Shehzad A, Ahn EM, Lee YM and Lee YS: Decursinol angelate inhibits LPS-induced macrophage polarization through modulation of the NFκB and MAPK signaling pathways. Molecules. 23(1880)2018.PubMed/NCBI View Article : Google Scholar | |
|
O'Connell RM, Taganov KD, Boldin MP, Cheng G and Baltimore D: MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci USA. 104:1604–1609. 2007.PubMed/NCBI View Article : Google Scholar | |
|
Hirano S, Zhou Q, Furuyama A and Kanno S: Differential regulation of IL-1β and IL-6 release in murine macrophages. Inflammation. 40:1933–1943. 2017.PubMed/NCBI View Article : Google Scholar | |
|
de la Haba C, Morros A, Martínez P and Palacio JR: LPS-induced macrophage activation and plasma membrane fluidity changes are inhibited under oxidative stress. J Membr Biol. 249:789–800. 2016.PubMed/NCBI View Article : Google Scholar | |
|
Zingarelli B and Cook JA: Peroxisome proliferator-activated receptor-gamma is a new therapeutic target in sepsis and inflammation. Shock. 23:393–399. 2005.PubMed/NCBI View Article : Google Scholar | |
|
Han X, Wu Y, Yang Q and Cao G: Peroxisome proliferator-activated receptors in the pathogenesis and therapies of liver fibrosis. Pharmacol Ther. 222(107791)2020.PubMed/NCBI View Article : Google Scholar | |
|
K C S, Kakoty V, Marathe S, Chitkara D and Taliyan R: Exploring the neuroprotective potential of rosiglitazone embedded nanocarrier system on streptozotocin induced mice model of Alzheimer's disease. Neurotox Res. 39:240–255. 2021.PubMed/NCBI View Article : Google Scholar | |
|
Yi JH, Park SW, Brooks N, Lang BT and Vemuganti R: PPARgamma agonist rosiglitazone is neuroprotective after traumatic brain injury via anti-inflammatory and anti-oxidative mechanisms. Brain Res. 1244:164–172. 2008.PubMed/NCBI View Article : Google Scholar | |
|
Peng Y, Chen L, Qu Y, Wang D and Zhu Y and Zhu Y: Rosiglitazone prevents autophagy by regulating Nrf2-antioxidant response element in a rat model of Lithium-pilocarpine-induced status epilepticus. Neuroscience. 455:212–222. 2021.PubMed/NCBI View Article : Google Scholar | |
|
Arcalis E, Ibl V, Hilscher J, Rademacher T, Avesani L, Morandini F, Bortesi L, Pezzotti M, Vitale A, Pum D, et al: Russell-like bodies in plant seeds share common features with prolamin bodies and occur upon recombinant protein production. Front Plant Sci. 10(777)2019.PubMed/NCBI View Article : Google Scholar | |
|
Song C, Chen J, Li X, Yang R, Cao X, Zhou L, Zhou Y, Ying H, Zhang Q and Sun Y: Limonin ameliorates dextran sulfate sodium-induced chronic colitis in mice by inhibiting PERK-ATF4-CHOP pathway of ER stress and NF-κB signaling. Int Immunopharmacol. 90(107161)2021.PubMed/NCBI View Article : Google Scholar | |
|
Kaplan J, Cook JA, O'Connor M and Zingarelli B: Peroxisome proliferator-activated receptor gamma is required for the inhibitory effect of ciglitazone but not 15-deoxy-Delta 12,14-prostaglandin J2 on the NFkappaB pathway in human endothelial cells. Shock. 28:722–726. 2007.PubMed/NCBI View Article : Google Scholar | |
|
Xia H, Ge Y, Wang F, Ming Y, Wu Z, Wang J, Sun S, Huang S, Chen M, Xiao W and Yao S: Protectin DX ameliorates inflammation in sepsis-induced acute lung injury through mediating PPARγ/NF-κB pathway. Immunol Res. 68:280–288. 2020.PubMed/NCBI View Article : Google Scholar | |
|
Liu WC, Wu CW, Fu MH, Tain YL, Liang CK, Hung CY, Chen IC, Lee YC, Wu CY and Wu KLH: Maternal high fructose-induced hippocampal neuroinflammation in the adult female offspring via PPARγ-NF-κB signaling. J Nutr Biochem. 81(108378)2020.PubMed/NCBI View Article : Google Scholar | |
|
Gonzalez Segura G, Cantelli BA, Peronni K, Rodrigo Sanches P, Komoto TT, Rizzi E, Beleboni RO, Junior WADS, Martinez-Rossi NM, Marins M and Fachin AL: Cellular and molecular response of macrophages THP-1 during Co-culture with inactive Trichophyton rubrum conidia. J Fungi (Basel). 6(363)2020.PubMed/NCBI View Article : Google Scholar | |
|
Pires BRB, Silva R, Ferreira GM and Abdelhay E: NF-kappaB: Two sides of the same coin. Genes (Basel). 9(24)2018.PubMed/NCBI View Article : Google Scholar |
