Isorhapontigenin from Traditionally used Iris Domestica Reduces the Inflammatory Response by Suppressing NF-κB and MAPK Signaling in LPS-Activated RAW 264.7 Macrophages

doi:10.21203/rs.3.rs-490290/v1

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Isorhapontigenin from Traditionally used Iris Domestica Reduces the Inflammatory Response by Suppressing NF-κB and MAPK Signaling in LPS-Activated RAW 264.7 Macrophages

https://doi.org/10.21203/rs.3.rs-490290/v1

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Background

Isorhapontigenin, a resveratrol analogue, isolated from Iris domestica can induce apoptosis in tumor cells. Here, we designed to explore whether isorhapontigenin reduced inflammatory response in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells.

Methods

Isorhapontigenin treated with RAW 264.7 cells, and then with LPS to stimulate inflammatory response. Proinflammatory cytokine expressions were measured using ELISA, and protein expressions were detected using western blots.

Results

Isorhapontigenin significantly inhibited the proinflammatory cytokine expressions. Isorhapontigenin also decreased cyclooxygenase-2 and inducible nitric oxide synthase productions and promoted heme oxygenase-1 expression in LPS-stimulated RAW264.7 cells. Isorhapontigenin could significantly inhibit NF-κB subunit p65 protein localization to the nucleus and reduced MAPK signal pathway activation. Isorhapontigenin also decreased reactive oxygen species production.

Conclusion

Thus, isorhapontigenin has potential anti-inflammation and anti-oxidative stress that inhibits inflammatory mediators and cytokines expressions through suppressing the MAPK and NF-κB pathways.

Nursing

anti-inflammation

isorhapontigenin

MAPK

NF-κB

proinflammatory cytokines

Inflammation can provide a dangerous signal, and inflamed cells or tissues can release inflammatory cytokines or inflammatory mediators to maintain or assist the immune system against microbial invasion [1]. However, excessive release of inflammatory cytokines may lead to dysplasia or continued chronic inflammatory diseases, such as obesity, non-alcoholic steatohepatitis, Alzheimer's disease, atherosclerosis, asthma, and cancer [2]. Therefore, regulating acute and chronic inflammation is of great importance to reducing tissue damage or relieving many chronic diseases. Macrophages are immune cells that are mainly activated by microbial infection or stimulatory molecules [3]. Macrophage activation during microbial infection suppresses the spread of microbes and also stimulates the inflammatory response of macrophages to regulate immune response activation [4]. In gram-negative bacterial infections, lipopolysaccharide (LPS) bind to macrophages, activating toll-like receptor 4 (TLR4) and inducing inflammatory signal pathway expression [5]. Activated macrophages also release excessive inflammatory mediators, chemokines, and cytokines to increase immune cell activation and immune cell function in infected tissues [6].

The nuclear transcription factor κB (NF-κB) is an important signaling pathway in macrophage-caused inflammatory response [7]. NF-κB is composed of two heterodimeric subunits, p65 and p50. When cells are not receiving a proinflammatory stimulus, p50 and p65 are captured by inhibitor of NF-κB (IκB), which suppresses NF-κB activation. When LPS binds to macrophages, it activates TLR4. This induces IκB phosphorylation, releasing p65 and p50 into the nucleus to switch on the gene expressions of inflammatory cytokines and other inflammatory mediators [8]. In addition, LPS-stimulation of macrophages also induces mitogen-activated protein kinase (MAPK) pathway activation, assisting in the expression of the NF-κB pathway and causing more severe inflammatory responses [9]. Therefore, regulating inflammatory signal pathway expression will improve the inflammatory response of macrophages.

Hemeoxygenase-1 (HO-1) is an antioxidant protein, and can be induced by various stresses that protects cells against oxidative stress [10]. Hence, HO-1 can protect oxidative stress and maintain cellular redox homeostasis [11]. Nuclear factor erythroid 2–related factor 2 (Nrf2) is a transcription factor, and LPS- or inflammatory cytokine-stimulated macrophages will increase Nrf2 translocation into the nucleus to regulate HO-1 expression to protect cells from oxidative damage [12].

Isorhapontigenin is a derivative of resveratrol found in some Chinese herbal medicines [13]. Previous studies pointed out that isorhapontigenin has anti-cancer, anti-oxidant and cardioprotective functions [14-16]. Another study found that isorhapontigenin can also inhibit airway epithelial cell inflammatory responses and reduce IL-6 expression in IL-1β-activated A549 cells [17]. Thus, isorhapontigenin is a natural product as an anti-inflammatory agent. However, the molecular mechanism of isorhapontigenin’s action on inflammatory macrophages remains unclear. Here, we would evaluate the anti-inflammatory molecular mechanism of isorhapontigenin and investigate inflammatory signaling expressions in RAW264.7 cells stimulated by LPS.

Cell cultures and cell viability

RAW 264.7 cells cultured in DMEM medium containing 10% FBS, and incubated at 37 °C and 5% CO2. Isorhapontigenin (≥98% purity)(Sigma, St. Louis, MO, USA) dissolved in DMSO solution, and the final DMSO concentration was ≤0.1% in the culture medium. Cell viability detected using CCK-8 assay kit (Sigma). Briefly, RAW 264.7 cells treated with (0-120μM) isorhapontigenin for 24 h. Next, cells added CCK-8 solution and cell viability was determined using a microplate spectrophotometer (Multiskan FC, Thermo Scientific, MA, USA).

Proinflammatory cytokine assay

RAW 264.7 cells treated with (0–20 μM) isorhapontigenin for 1 h. Next, 100 ng/mL LPS (Escherichia coli 055:B5, Sigma) stimulated the cells, and cultured for 8 h to detect IL-6 and TNF-α expression, and cultured 24 h to detect PGE₂ and IL-1β production by ELISA kits (R&D Systems, Minneapolis, MN, USA). SP600125 (JNK inhibitor), SB203580 (p38 inhibitor), and PD98059 (ERK inhibitor) (Sigma) treated with or without 10 μM isorhapontigenin to assay IL-6 and TNF-α production. Specific cytokine or PGE₂ were determined using a microplate spectrophotometer (Thermo Scientific).

Nitrite assay

Cells treated with isorhapontigenin (0–20 μM) for 1 h. Next, cells stimulated with 100 ng/mL LPS (Sigma) for 24h. The supernatant treated with the Griess reagent (Sigma) for 15min, and nitrite levels was detected at 570 nm, a microplate spectrophotometer (Thermo Scientific).

Preparation of total and nuclear protein

Cells treated with isorhapontigenin for 1 h. Next, cells stimulated with or without 100 ng/mL LPS for 30 min to detect protein phosphorylation, or for 24 h to investigate total protein expression. Briefly, cells collected and lysed using protein lysis buffer containing phosphatase inhibitor cocktail (Thermo Scientific). Furthermore, nuclear proteins isolated using NE-PER cell fractionation kits (Thermo Scientific).

Western blotting

Protein separated using SDS-PAGE gel and the protein bands transferred to PVDF membranes. The membranes incubated with specific antibodies, including ERK1/2, JNK, p38, ICAM-1, inducible nitric oxide synthase (iNOS), phosphorylated-ERK 1/2, phosphorylated-JNK, and phosphorylated p38 (Cell Signaling, MA, USA), cyclooxygenase-2 (COX-2), and β-actin (Sigma), IκB-α, lamin B1, HO-1, phosphorylated-IκB-α, and Nrf2 (Santa Cruz, CA, USA). Following washing, membranes incubated with secondary antibodies, and finally proteins were presented using enhanced chemiluminescence solution (Thermo Scientific) and the BioSpectrum imaging system (UVP, Upland, CA, USA).

ROS expression

Cells treated with isorhapontigenin for 1 h, then cells stimulated with LPS for 24 h. Cells washed and added with DCFH-DA as described previously [18]. ROS expressions observed using fluorescence microscopy (Olympus). Cells also detected ROS levels using the multimode plate readers (BioTek synergy HT). Furthermore, MAPK inhibitors (Enzo Life Sciences) were treated with or without 10 μM isorhapontigenin to detect ROS expression.

Immunofluorescence staining

Cells were used to seed microscope slides in culture plates and incubated with isorhapontigenin for 1 h, then LPS stimulated cells for 24 h. The slides treated with a specific P65 antibody (1:100), followed by a fluorescent secondary antibody. Finally, the slides treated with DAPI solution for nuclear staining and presented images using fluorescence microscope (Olympus).

Statistics

Experimental results performed at least three independent experiments. Data are presented as the mean ± SD. Statistical analysis of experimental data performed using one-way ANOVA followed by Dunnett’s test and post hoc analysis. Statistical significance defined as p < 0.05.

Effects of isorhapontigenin on cell viability

Isorhapontigenin did not effectively affect cell viability at concentrations ≤40 μM (Fig. 1a). Hence, cellular experiments used concentrations of isorhapontigenin from 0–20 μM.

Isorhapontigenin decreased proinflammatory cytokines expressions

10–20 μM isorhapontigenin had an inhibitory effect on IL-1β concentrations in LPS-stimulated RAW 264.7 cells (Fig. 1b). Furthermore, isorhapontigenin also significantly reduced the IL-6 and TNF-α levels in a concentration-dependent manner (Fig. 1c–d).

Isorhapontigenin decreased COX-2 and iNOSexpression

Isorhapontigenin significantly suppressed nitrite and PGE₂ expressions (Fig. 2a-b). Isorhapontigenin also significantly attenuated COX-2 and iNOS expression compared to LPS-induced RAW 264.7 cells (Fig. 2c-e).

Isorhapontigenin attentuates IκBα phosphorylation and NF-κB activation

The results demonstrated that isorhapontigenin significantly reduced IκB-α degradation and phosphorylation compared to LPS-incubated RAW 264.7 cells (Fig. 3). Furthermore, p65 was mostly cytoplasmic in LPS unstimulated cells, while its level in nucleus increased after treatment with LPS. Interestingly, western blotting of cytosolic and nuclear fractions demonstrated that the nuclear translocation of p65 decreased in isorhapontigenin-treated compared with untreated LPS-induced cells (Fig. 4a–c), and comparison of fluorescent staining of p65 in cells under these conditions confirmed the significant suppression of nuclear translocation of p65 by isorhapontigenin (Fig. 4d).

Isorhapontigenin regulated the phosphorylation of MAPK pathway

Isorhapontigenin effectively decreased the phosphorylation of ERK1/2, JNK, and p38 (Fig. 5a-b). Therefore, we used MAPK inhibitors to investigate how isorhapontigenin attenuates proinflammatory cytokine expression. The resulted demonstrated that isorhapontigenin enhanced the ability of MAPK inhibitors to suppress IL-6 and TNF-α expression, respectively (Fig. 5c-d).

Isorhapontigenin increased Nrf2 and HO-1 production

We found that isorhapontigenin significantly promoted HO-1 levels in cytoplasm and increased Nrf2 expressions in nucleus compared with LPS-stimulated macrophages (Fig. 6a–c). In cells treated with DCFH-DA, fluorescence microscopy revealed that isorhapontigenin could decrease intracellular ROS expressions (Fig. 6d). RAW 264.7 cells also incubated with DCFH-DA solution, and detected ROS expressions using Multi-Mode microplate reader. The result demonstrated that isorhapontigenin effectively reduced ROS expressions in LPS-stimulated RAW 264.7 cells (Fig. 6e). Furthermore, when isorhapontigenin added with MAPK inhibitors, ROS productions effectively decreased more effectively compared to isorhapontigenin treated with LPS-activated RAW 264.7 cells (Fig. 6f).

Isorhapontigenin is a tetrahydroxylated stilbenoid isolated from I. domestica, G. cleistostachyum, and wine grapes [19]. Isorhapontigenin has been known to have anticancer, anti-inflammatory, antioxidant effects [14, 20, 21]. Isorhapontigenin was found that could inhibited cartilage matrix damage and chondrocyte inflammation in rats, suppressing COX-2 and iNOS expression in IL-1β-induced chondrocytes [17]. However, anti-inflammatory molecular mechanism of isorhapontigenin on immune cells is not yet fully clear. In this current study, isorhapontigenin significantly reduced pro-inflammatory cytokine productions by LPS-stimulated macrophages. In addition, in LPS-stimulated macrophages, isorhapontigenin also reduced iNOS and COX-2 productions, and increased HO-1 and Nrf2 protein expression. We also found that isorhapontigenin significantly attenuated the nuclear translocation of p65 and decreased MAPK phosphorylation in inflammatory signaling pathways, and improved the nuclear translocation of Nrf2 to promote its antioxidant effect in LPS-induced macrophages.

When infecting bacteria invade human tissues or organs, innate immune system detect and devour them, preventing bacterial spread, and reducing the likelihood of diseases such as sepsis and bacteremia [5]. The LPS binds to the TLR4 receptor of macrophages, activated inflammatory signaling and released inflammatory mediators and cytokines to promote the ability of immune cells to resist bacterial infection [22]. LPS-stimulated macrophages can induce excessive iNOS expression, and iNOS can convert L-arginine to L-citrulline and produce NO [23]. These NO molecules in turn activate inflammatory molecular messages to inform inflammatory cells and tissues of danger, interfering with the normal physiological functions of tissues [24]. Previous research found that isorhapontigenin could reduce NO and iNOS expression in IL-1β-induced rat chondrocytes [17]. In this study, isorhapontigenin significantly inhibited iNOS expression in LPS-stimulated macrophages, and thus could reduce the expression of inflammatory signaling pathways caused by excessive NO. In addition, LPS-stimulated macrophages can also strongly increase COX-2 expression [25]. COX-2 metabolizes arachidonic acid to produce PGE₂, which increases pain in inflamed tissue and causes vasodilation, allowing increased immune-cell migration into the tissue [26]. COX-2 inhibitors as anti-inflammatory and analgesic drugs can decrease PGE₂ production by inhibiting COX-2 expression, thus reducing inflammation [26]. Isorhapontigenin was reported to reduce COX-2 and PGE₂ expression and reduce IL-1β-induced rat cartilage explant damage [17]. Our experiments also found that isorhapontigenin inhibits COX-2 and PGE₂expressions in LPS-activated macrophages. Hence, isorhapontigenin has the ability to reduce secretions of macrophage inflammatory mediator and thus reduce the excessive activation of immune cells.

During bacterial infection, activated macrophages release inflammatory cytokines, which cause more immune cell activation and severe inflammation [27]. LPS-stimulated macrophages can express high levels of TNF-α to increase the permeability of vascular endothelial cells and promote their expression of cell adhesion molecules. This allows more neutrophils or monocytes to infiltrate the infected tissue to promote immunity and attack microorganisms [28]. However, bacterial infection induces excessive activation of macrophages, which release excessive amounts of TNF-α, causing fever, lowered blood pressure, and even organ necrosis, sepsis, and death [22, 29]. Therefore, reducing the uncontrolled activation of macrophages would reduce the excessive production of TNF-α and reduce the risk of death from organ failure and shock [30]. In this study, 5–20 μM isorhapontigenin inhibited TNF-α production in LPS-induced macrophages. Isorhapontigenin is an analog of resveratrol. Previously, scholars found that 1–25 μM resveratrol can reduce the secretion of TNF-α by LPS-stimulated macrophages [31]. Therefore, we thought that isorhapontigenin should also have a good anti-inflammatory effect. Inflamed macrophages also release a large amount of IL-6. IL-6 is considered to be an important factor in the expression of C-reactive protein, which initiates acute inflammation [32]. In some patients with chronic obstructive pulmonary disease, the lungs contain large amounts of C-reactive protein and IL-6, which stimulate vasodilation and aggravate inflammation [33]. In addition, LPS-induced macrophages secrete IL-1β to stimulate the hypothalamus to increase body temperature and promote the innate immune response against bacterial infection [34]. IL-1β can also induce lung neutrophil infiltration and increase lung inflammation in mice with LPS-induced lung injury [35]. This study also found that 10–20 μM isorhapontigenin inhibited the production of IL-1β and IL-6 by inflammatory macrophages. Therefore, isorhapontigenin may be a natural anti-inflammatory compound that can reduce inflammation during bacterial infections.

NF-κB can be translocated to the nucleus where it induces the expression of inflammation-related genes, including those encoding proinflammatory cytokines, iNOS, and COX-2 [7]. LPS binds to the CD14 molecule on macrophages, activating TLR4, which triggers signaling through the NF-κB pathway [36, 37]. In inactivated macrophages, IκB (composed of IκB-α and IκB-β subunits) inhibits NF-κB activity, restricting it to the cytoplasm. LPS stimulates IκB phosphorylation and release, allowing NF-κB to enter the nucleus to drive the expression of inflammation-related gene expression [36]. In this current study, isorhapontigenin inhibited IκB phosphorylation and suppressed IκB degradation. Therefore, in inflammatory macrophages treated with isorhapontigenin, most NF-κB remained in the cytoplasm, attenuating the expression of inflammation-related genes. To further confirm that isorhapontigenin can reduce NF-κB translocation into the nucleus of inflamed macrophages, we used immunofluorescent staining to demonstrate that isorhapontigenin treatment reduces p65 protein expression in the nucleus of LPS-stimulated macrophages. Recent studies demonstrated that the NF-κB pathway is important in regulating the increased expression of COX-2 and iNOS in activated macrophages [38]. Previous studies have found that MAPK signaling also promotes NF-κB activity in these calls. We found that isorhapontigenin treatment of LPS-stimulated macrophages significantly reduced JNK, ERK 1/2, and p38 phosphorylation. Additionally, MAPK inhibitors co-cultured with isorhapontigenin and found that isorhapontigenin addition decreased proinflammatory cytokine expression. Thus, our results show that isorhapontigenin reduces the expression of inflammatory mediators and cytokines by inhibiting the NF-κB and MAPK pathways.

HO-1 protein expression is induced under various stresses. Stimulation of macrophages by inflammation or oxidative molecules induces massive expression of HO-1 [39]. HO-1 metabolizes heme to produce carbon monoxide, biliverdin, and iron [10]. Resveratrol can stimulate macrophages to express a large amount of HO-1, inhibit the production of iNOS, COX-2, and TNF-α, and reduce the expression of ROS in LPS-induced macrophages [31]. Recent studies demonstrated that Nrf2 is an essential transcription factor for regulated antioxidant pathway [40]. Nrf2 translocation into the nucleus to regulate the expression of HO-1, which enhances the cell’s antioxidant ability [12]. In addition, isorhapontigenin added together with MAPK inhibitors could significantly attenuate ROS productions in LPS-stimulated macrophages. Therefore, our results indicate that isorhapontigenin promotes the nuclear translocation of Nrf2 and induces HO-1 synthesis in macrophages, thus reducing the levels of ROS via blocked MAPK signal pathways in LPS-stimulated macrophages.

In conclusion, isorhapontigenin reduced proinflammatory cytokine and mediator expression by suppressing of the activation of the MAPK and NF-κB signaling pathways in LPS-stimulated macrophages. Isorhapontigenin could decreased ROS levels by upregulating the Nrf2/HO-1 pathway (Figure 7). Hence, isorhapontigenin has anti-inflammatory and antioxidant activity and is a potential novel anti-inflammatory agent.

COMPLIANCE WITH ETHICAL STANDARDS

Ethics Approval and Consent to Participate

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Consent for publication

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Availability of data and materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Competing interests

The authors have no conflicts of interest to declare.

Funding

This study was supported in part by grants from the Chang Gung Memorial Hospital (CMRPF1F0083, CMRPF1G0181, CMRPF1H0023, and CMRPF1H0043) and the Chang Gung University of Science and Technology (ZRRPF3K0011 and ZRRPF3K0111-7), and the Ministry of Science and Technology in Taiwan (109-2320-B-255-006-MY3).

Authors' contributions

Designed and performed the experiments: WCH, SH, and CJL; Analysis and interpretation of data: WCH, SJW, HL and HLP; Drafting the manuscript: SH, and CJL.

Acknowledgements

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Isorhapontigenin from Traditionally used Iris Domestica Reduces the Inflammatory Response by Suppressing NF-κB and MAPK Signaling in LPS-Activated RAW 264.7 Macrophages

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