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Investigation of sanguinarine and chelerythrine effects on LPS-induced inflammatory gene expression in THP-1 cell line.

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Keywords: Benzo[c]phenanthridine alkaloids Inflammation RT-qPCR CCL-2 IL-6

ABSTRACT

Quaternary benzo[c]phenanthridine alkaloids sanguinarine and chelerythrine have been used in folk medicine for their wide range of useful properties. One of their major effect is also anti-inflammatory activity, that is not clarified in detail.

This study focused on the ability of these alkaloids to modulate the gene expression of pro-inflammatory tumour necrosis factor a (TNF-[alpha]), monocyte chemoattractant protein 1 (MCP-1, also known as CCL-2), interleukin (IL)-6, IL-1[beta] and anti-inflammatory cytokines IL-1 receptor antagonist (IL-1RA) and IL-10. The effect of these alkaloids was compared with that of conventional drug prednisone.

Human monocyte-derived macrophages were pre-treated with alkaloids or prednisone and inflammatory reaction was induced by lipopolysaccharide. Changes of gene expression at the transcriptional level of mentioned cytokines were measured.

In our study mainly affected pro-inflammatory cytokines were CCL-2 and IL-6. Two hours after LPS stimulation, cells influenced by sanguinarine and chelerythrine significantly declined the CCL-2 expression by a factors of 3.5 ([p < 0.001) and 1.9 (p < 0.01); for those treated with prednisone the factor was 5.3 (p < 0.001). Eight hours after LPS induction, both alkaloids significantly diminished the CCL-2 expression. The lower expression was found for sanguinarine--lower by a factor of 4.3 than for cells treated with the vehicle (p < 0.001).

Two hours after LPS stimulation, cells treated with sanguinarine decreased the IL-6 mRNA level by a factor of 3.9 (p < 0.001) compared with cells treated with the vehicle. Chelerythrine decreased the level of IL-6 mRNA by a factor of 1.6 (p < 0.001). Sanguinarine decreased gene expression of CCL-2 and 1L-6 more than chelerythrine and its effect was quite similar to prednisone. Four hours after LPS stimulation, cells pre-treated with sanguinarine exhibited significantly higher expression (a factor of 1.7, p < 0.001) of IL-1RA than cells without sanguinarine treatment. Our results help to clarify possible mechanisms of action of these alkaloids in the course of inflammation.

[c] 2012 Elsevier GmbH. All rights reserved.

Introduction

Inflammation is a common causation of many diseases and natural compounds with anti-inflammatory activities are large and important group of pharmaceuticals.

Sanguinarine (1) and chelerythrine (2) are quaternary benzo[c]phenanthridine alkaloids (QBA) (Figs. 1 and 2) widely distributed in the plants of the Papaveraceae, Fumariaceae, Routaceae, Ranunculaceae and Meliaceae families. The richest sources of these alkaloids can be mentioned--Sanguinaria canadensis L., Dicranostigma lactucoides Hook F. et Thomas, Chelidonium majus L., Macleaya cordata (Willd.) R.Br, Macleaya microcarpa (Maxim.) Fedde, Sty-lophorum lasiocarpum (Oliv.) Fedde and some species of genus Bocconia. All these species belong to the family Papaveraceae (Dostal and Potatek 1990). Extracts from some plants containing 1 and 2 have been used for centuries in folk medicine for their wide range of useful properties, such as antimicrobial, antifungal, anti-inflammatory and antitumour effects (Walterova et al. 1995). Some commercial toothpastes and oral rinses containing Sanguinaria extract are shown to be effective against plaque build-up and gingivitis (Kuftinec et al. 1990)

Biological activities of these alkaloids have been described in many studies. Their antimicrobial activity comprises Gram-positive and Gram-negative bacteria, as well as yeasts, fungi and viruses (Colombo and Bosisio 1996). 1 and 2 exhibit effect on the cytoskeleton with potential for interference with microtubule assembly. Inhibition of taxol-mediated polymerization of rat brain tubulin by a reversible interaction with its thiol groups was observed (Wolf and Knipling 1993). Sanguinarine (1) forms a molecular complex with DNA by intercalation, specifically binding to regions rich in guanosine-cytosine (Maiti and Kumar 2007).

Over the last years, studies on sanguinarine (1) and chelerythrine (2) have focused also on their potential as anti-cancer drugs. Antiproliferative activities have been demonstrated in cells derived from various human carcinoma, e.g. cervical (Ding et al. 2002), lymphoma (Hussain et al. 2007), colon (Matkar et al. 2008) and melanoma (Hammerova et al. 2011). Apoptosis induction by 1 was mediated via modulations in Bc1-2 family proteins, releasing mitochondrial cytochrome c and activation of caspase 3 (Adhami et al. 2003).

The mechanism of anti-inflammatory activity of these alkaloids is not fully understood yet, but there are some studies elucidated this effect. I blocked the TNF-induced phosphorylation and degradation of IkB[alpha], an inhibitory subunit of NF-k[beta], which is a pleiotropic transcription factor and whose activation results in inflammation, and inhibited translocation of p65 subunit to nucleus (Chaturvedi et al. 1997). Other experiments have shown that QBAs have the capability to bind to glucocorticoid receptor and induce its nuclear translocation, but they lack capacity to turn-on the transcriptional activity of this receptor (Dvorak et al. 2006). Inhibition of two important enzymes 5- and 12-lipoxygenase (LOX) has been described (Vavreckova et al. 1996).

This study is focused on affection of gene expression of inflammatory-related cytokines at the transcription level. Under investigation were pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-[alpha]), interleukin (IL)-1[beta], monocyte chemoat-tractant protein 1 (MCP-1, also known as CCL-2), IL-6 and anti-inflammatory cytokines IL-1 receptor antagonist (IL-1RA) and IL-10. TNF-[alpha] acts as a one of key mediators in the inflammatory immune response (Strieter et al. 1993). The other genes (proteins) were IL-1[beta] and IL-1RA, which act antagonistically. The balance between IL-1[beta] and IL-IRA plays an important role in the normal physiology of various organs and tissues. Overproduction of IL-1 and/or underproduction of IL-1RA predisposes to the development of various diseases, e.g. arthritis, inflammatory bowel disease, leukaemia, osteoporosis, diabetes, diseases of the liver and pancreas or central nervous system diseases (Arend 2002). Role of CCL-2 in monocyte recruitment, activation and migration during infection or under other inflammatory conditions is well known. I1-6 is also a key player in an inflammation; it is the main inducer of acute-phase protein synthesis. Many studies have found that IL-6 overproduction tends to the development of chronic autoimmune and inflammatory diseases. The last studied cytokine was IL-10 with anti-inflammatory properties reduces the production of pro-inflammatory mediators and inhibits antigen presentation. Additionally, IL-10 plays an important role in the biology of B and T lymphocytes (Moore et al. 2001). The model used to study induced inflammation was stimulation of macrophages by lipopolysaccharides (LPS) obtained from Gram-negative bacteria Escherichia coli. LPS acts as the prototypical endotoxin, it binds the CD14/TLR4/MD2 receptor complex which promotes the secretion of pro-inflammatory cytokines in many cell types, but especially in macrophages (Stewart et al. 2006). The action of 1 and 2 was compared with conventional drug prednisone.

Materials and methods

Material

The RPMI 1640 medium, penicillin-streptomycin mixture, and trypsin 170 U/ml supplemented with EDTA 200 [micro]g/ml were purchased from Lonza (Verviers, Belgium).

Phosphate-buffered saline (PBS), foetal bovine serum (FBS), phorbol myristate acetate (PMA), indomethacin, Erythrosin B, and the lipopolysaccharide (LPS) obtained from Escherichia coli 0111:B4 were purchased from Sigma-Aldrich (Steinheim, Germany).

Sanguinarine (1) and chelerythrine (2) were isolated in authors' laboratory by preparative column chromatography (Dostal et al. 1992). Purity of 1 and 2 was not under 98% according to the HPLC analysis.

An RNeasy Plus Mini Kit (Qiagen, Hilden, Germany) was used for isolation of total RNA from frozen samples. Reverse transcription quantitative PCR (RT-qPCR) was accomplished with a TaqMan RNA-to-[C.sub.T] 1-Step Kit from Applied Biosystems (Cheshire, UK) and TaqMan Gene Expression Assays from Applied Biosystems (Foster City, CA) were used for these reactions, specifically Hs00174128_m1 was used for TNF-[alpha], Hs00234140_m1 for CCL2, Hs00985639_m1 for IL-6, Hs00961622_m1 for IL-10, Hs01555410_m1 for IL-1[beta] (3, Hs00893626_m1 for IL-1RA gene expression quantification. [beta]-Actin, assay number 4326315E served as an internal control for gene expression.

Maintenance of cell culture and differentiation to macrophages

The THP-1 human monocytic leukaemia cell line was obtained from the European Collection of Cell Cultures (ECACC, Salisbury, UK). The cells were cultivated at 37[degrees]C in RPMI 1640 medium supplemented with 2 mM L-glutamine, 10% FBS, 100 U/ml of penicillin and 100 [micro]g/ml of streptomycin in a humidified atmosphere containing 5% [CO.sub.2]. The viability of cells was greater than 94% throughout the experiment.

Stabilized cells (5th-20th passage) were split into 96-well plates to afford the concentration of 100 000 cells/mt, and cultivated for 72 h. Differentiation into macrophages was induced by phorbol myristate acetate (PMA) at final concentration 50 ng/ml and cells were incubated for another 24 h. In comparison with monocytes, differentiated macrophages tend to adhere to the bottoms of the cultivation plates. For the next 24 h the cells were incubated with fresh complete RPM! medium, i.e. containing antibiotics and FBS, without PMA. The medium was then aspirated and the cells were washed with PBS and cultivated for another 24h in serum-free RPM! 1640 medium. These prepared macrophages were used for the follow-up experiments (Hosek et al. 2010).

Cytotoxicity test

Tested compounds 1 and 2 were dissolved in dimethylsulphox-ide (DMSO) at 6 concentrations ranging 0.1-5 [micro]M and added to monocytes suspension (200 000 cells/ml). The concentration of DMSO did not exceed 0.1% in the culture medium. The toxic effect of 1 and 2 was measured by erythrosine exclusion test after 24 h and the [LD.sub.50] value was calculated as describe previously (Hoek et al. 2011).

Drug treatment and induction of inflammation

Differentiated macrophages were pre-treated for 1 h with 0.5 [micro]M 1 and 1.5 [micro]M 2 dissolved in (DMSO). The cytotoxic test showed that these concentrations have negligible cytotoxic effect and accord with 85% viability.

For comparison with a conventional drug, 1[micro]M prednisone dissolved in DMSO was used. Control cells contained a vehicle (DMSO) only. The concentration of DMSO was 0.1% in each well. The effect of 1 and 2 on the modulation of inflammatory gene expression was tested by adding 1[micro]g/ml LPS dissolved in water to drug-pretreated macrophages. The alkaloids remained in the medium after LPS stimulation. Control cells remained without LPS stimulation and were used for determination of basal gene expression. Cell samples were harvested by trypsinization and scraping 2, 4 and 8h after the LPS treatment. Cells were spun down, supernatant was removed and pelleted cells were frozen in liquid nitrogen and stored at -80 [dregees]C for further processing.

Quantification of gene expression

The gene expression was quantified by using one-step reverse-transcription quantitative polymerase chain reaction (RT-qPCR) with TaqMan Gene Expression Assays which contains specific primes and probes. A total of 4 [micro]l of isolated RNA were added to 21 [micro]l of the PCR reaction mixture containing both reverse transcriptase and DNA polymerase. The parameters for the RT-qPCR were set up according to the manufacturer's recommendations: 48 [degrees]C for 15 min, 95 [degrees]C for 10 min, followed by 40 cycles at 95 [degrees]C for 15 s and 60 [degrees]C for 1 min. Results were normalized to the amount of [beta]-actin and the change in gene expression was determined by the [DELTA][DELTA][C.sub.T] method using StepOne Software, version 2.1 (Applied Biosystems). Relative gene expression of control cells (without LPS treatment) was adjusted as 1. This value is not shown in graphs.

Statistical analysis

The results are expressed as the mean [+ or -] SE of experiments carried out in triplicates. The statistical significance was tested using the one-way ANOVA with Tukey post hoc test for comparisons between the means, and the differences between the two conditions were retained for p < 0.05. The statistical significance was determined at levels of p <0.05, p < 0.01, and p <0.001. GraphPad Prism 5.01 (GraphPad Software Inc., San Diego, CA) was used to perform the analysis.

Results

First of all, cytotoxic effect of 1 and 2 against human monocytic leukaemia cells (THP-1) was tested. The [LD.sub.50] values were determined as 0.83 [micro]M for sanguinarine (1) and 3.4611, M for chel-erythrine (2). The doses of alkaloids caused no more than a 15% decrease in cell viability were used as a non toxic for further experiments (Figs. 3 and 4).

The relative changes in the gene expression of TNF-[alpha] for LPS-stimulated cells were compared to those for vehicle-treated cells. The influence of 1 and 2 on this expression is summarized in Fig. 5. Both alkaloids non-significantly decreased the TNF-[alpha] expression, sanguinarine (1) by a factor of 1.6 and chelerythrine (2) by only a factor of 1.3 2h after the LPS-induced inflammation. A nonsignificant decrease was also observed for the prednisone-treated cells. After 4 h, expression of mRNA for TNF-[alpha] increased. Eight hours after LPS induction, cells influenced by sanguinarine (1) showed non-significant lower expression by a factor of 1.5 than was found for cells treated with vehicle alone.

The influence of 1 and 2 on expression of another pro-inflammatory gene CCL-2 is summarized in Fig. 6. Two hours after LPS stimulation, cells influenced by sanguinarine (1) and chelerythrine (2) significantly declined the CCL-2 expression by a factors of 3.5 (p < 0.001) and 1.9 (p < 0.01): for those treated with prednisone the factor was 5.3 (p < 0.001). Four hours after LPS stimulation, statistically significant lower expression of CCL-2 mRNA were detected only for the 1 and prednisone (p <0.001). Eight hours after LPS induction, both alkaloids significantly diminished the CCL-2 expression. The lower expression was found forllower by a factor of 4.3 than for cells treated with the vehicle (p <0.001). Prednisone significantly decreased the level of CCL-2 mRNA by a factor of 32.2 (p <0.001).

Results of influencing the expression of pro-inflammatory cytokine IL-6 by 1 and 2 are shown in Fig. 7. Two hours after the LPS stimulation, both alkaloids and prednisone significantly declined the 1L-6 expression. Cells treated with 1 decreased the IL-6 mRNA level by a factor of 3.9 (p < 0.001) compared with cells treated with the vehicle. 2 decreased the level of IL-6 mRNA by a factor of 1.6 (p <0.001). After 4 and 8 h after the LPS stimulation, both alkaloids non-significantly decreased the IL-6 expression. Statistically significant lower expressions of IL-6 mRNA were detected only for the prednisone treatments after 4 h (p <0.001) and 8 h (p <0.05).

Last studied pro-inflammatory cytokine was 1L-1[beta]. However, pre-treatment with 1 and 2 have not affected the transcription of this gene (data not shown).

It was subsequently investigated the gene expression of antiinflammatory cytokine IL-1RA. The influence of 1 and 2 on this expression is summarized in Fig. 8. Four hours after LPS stimulation, cells pre-treated with 1 exhibited significantly higher expression (a factor of 1.7, p <0.001) of IL-1RA than cells without sanguinarine (1) treatment. Chelerythrine (2) increased the level of IL-1RA mRNA only by a factor of 1.4, which was not statistically significant. Eight hours after LPS induction, prednisone significantly diminished the IL-1RA expression by a factor of 3.2 (p <0.001) whereas 1 and 2 had similar values as vehicle-treated cells.

The last cytokine under the investigation was anti-inflammatory cytokine IL-10. The results are summarized in Fig. 9. Prednisone significantly decreased the expression of mRNA for IL-10 2 h after LPS stimulation (a factor of 2.4, p < 0.01); cells influenced by I showed decrease the level of IL-10 mRNA only by a factor of 2.3, which was not statistically significant. Four hours after LPS induction, cells stimulated by 1 and 2 increased the expression of IL-10 only by factors of 1.7 and 1.3, which was not statistically significant. Eight hours after LPS induction both alkaloids non-significant increased the expression of IL-10.

Discussion

Sanguinarine (1) and chelerythrine (2) are biologically active substances in preparations used in the treatment of dental plaque formation and inflammatory periodontal diseases, but the mechanism of anti-inflammatory activity of these alkaloids is still not known in details. The present study focused on affection of gene expression of inflammatory-related cytokines at the transcription level.

Monocytes and macrophages are found in higher numbers in active periodontal lesions and play an important role in the host inflammatory response to periodontopathogens (Silva et al. 2007). Monocytes/macrophages cell lines are commonly used in testing anti-inflammatory activity of natural substances (Bodet et al. 2008; Hokk et al. 2010). THP-1 cell line was chosen for its similar to native immune cells (Auwerx 1991).

Cytotoxicity assay showed that cytotoxic effect of sanguinarine (1) was much higher than that of chelerythrine (2) in THP-1 cells and both alkaloids inhibited viability in dose-dependent manner, which is consistent with other studies (Malikova et at. 2006; Slaninova et at. 2001). Both alkaloids interact in a planar, cationic form with the nuclear and mitochondrial DNA by intercalation mechanism. Intercalating properties of 1 and 2 correlate with their cytotoxic activity and ability to induce breaks in DNA (Kaminskyy et al. 2006). Different toxicity and intercalation of these alkaloids can be caused by differences in their structure. An important geometric parameter of the structures of alkaloids is the orientation of substituents in positions 2.3 and 7.8. They line at the same plane as the aromatic ring with the exception of methoxy group on the carbon C7. This group is oriented almost upright to the plane (Toukk et at. 2002). 2 contains methoxy group at C7 position and has a lower possibility of intercalation into DNA. This assumption is confirmed by the results of microscopic study, which showed that 2 reluctantly penetrates into the cell nucleus and its fluorescence is weak and unstable. On the contrary, 1 incorporates rapidly into the nucleus and the fluorescence is bright (Slaninova et al. 2007).

Moreover it can be assumed that toxicity is cell-dependent and sensitivity of various cells to tested compounds might be different--the [IC.sub.50] value for 1 is 6.3 [+ or -] 1.4 in human prostate cancer cell lines LNCaP and 1.2 [+ or -] 0.4 in gingival fibroblasts. For 2, values of IC50 are at least three times higher for both cell lines than for 1 (Malikova et al. 2006).

Activation of the NF-kB plays a central role in inflammation through its ability to induce transcription of pro-inflammatory genes and is also responsible of Th1-dependent delayed-type hypersensitivity. Synthesis of cytokines (TNF-[alpha], CCL-2, 1L-1[beta] and IL-6) is mediated by this transcription factor (Tak and Firenstein 2001). 1 and 2 cause an increase in nuclear levels of NF-kB (Dvorak et al. 2006), and in our study, both alkaloids non-significantly increased TNF-a expression 4 h after LPS stimulation, 1 increased this expression more than 2. In addition, expression of IL-1[beta] was unaffected by any alkaloid tested. Paradoxically at this case, the behaviour of these alkaloids is rather pro-inflammatory. On the other hand, pro-inflammatory IL-6 gene is also under the transcriptional control of NF-kB and sanguinarine (1) decreased at least three times the production of mRNA 2 h after LPS stimulation. IL-6 can act on the vascular endothelial cells, these activation leads to the production of chemokines and adhesion molecules, which promote leukocyte recruitment to the site of inflammation (Lipsky 2006). Another important finding is the effect of 1 and 2 on attenuating the transcription of pro-inflammatory CCL-2. 1 decreased expression of this cytokine more than 2. CCL-2 has been implicated in the pathogenesis of chronic diseases characterized by monocytic infiltrates, like psoriasis or rheumatoid arthritis (Xia and Sui 2009). Both alkaloids are therefore likely to be engaged in monocyte recruitment to sites of infection and inflammation.

The ratio between IL-1RA and IL-1 influences normal physiology of various organs and tissues, e.g. arthritis, inflammatory bowel disease, leukaemia, diabetes, or central nervous system diseases (Arend 2002). Our study shows that 1 can slightly increase the expression of IL-1RA and therefore increases this ratio in favour of IL-1RA. On the other hand, IL-1RA must be produced in tissues in abundance to block the effect of IL-1 (Arend 2002), and thus this mechanism rather slightly promotes anti-inflammatory effect of these alkaloids.

In conclusion, this study deals with the effect of sanguinarine (1) and chelerythrine (2) on gene expression of several pro-and anti-inflammatory cytokines. Based on our results, mainly affected cytokines are CCL-2, IL-6 and IL-IRA, while sanguinarine (1) has higher anti-inflammatory potential and in some ways can be comparable with prednisone. This paper helps to clarify possible mechanisms of action of these alkaloids in the course of inflammation.

Acknowledgements

The financial support of this work by the Czech Science Foundation (Project No. GA525/08/0819) and by the Masaryk University project of specific research MU/A/0963/2010 is gratefully acknowledged.

Abbreviations: DMSO, dimethylsulphoxide; FBS, foetal bovine serum; IL interleukin; LPS, lipopolysaccharide; MCP-1, monocyte chemoattractant protein 1; PBS, phosphate-buffer saline; PCR, polymerase chain reaction; PMA, phorbol myristate acetate; RT-qPCR, reverse transcription quantitative polymerase chain reaction; THP-1, human monocyte leukaemia cell line; TNF-[alpha], tumour necrosis factor [alpha].

* Corresponding author. Tel.: +420 549 495 961.

E-mail address: k.pencikova@mail.muni.cz (K. Peaikova).

0944-7113/$--see front matter 0 2012 Elsevier GmbH. All rights reserved.

http://dx.doi.org/10.1016/j.phymed.2012.04.001

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K. Pentlkova (a), (*), P. Kolldr(b), V. Muller lavalova (b), E. Tdborskda (J). Urbanova (c), J. Hosek (d)

(a) Department of Biochemistry, Faculty of Medicine, Masaryk University, Kamenice 5/A16, 625 00 Brno, Czech Republic

(b) Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackeho 1-3, Brno 612 42, Czech Republic

(c) Department of Chemistry. Faculty of Science, Masaryk University, Kamenice 5/A14, 625 00 Brno, Czech Republic

(d) Department of Natural Drugs. Faculty of Pharmacy. University of Veterinary and Pharmaceutical Sciences Brno, Palackeho 1-3, Brno 612 42, Czech Republic
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Title Annotation:human acute monocytic leukemia cell line; lipopolysaccharides
Author:Pencikova, K.; Kollar, P.; Zavalova, Muller V.; Taborska, E.; Urbanova, J.; Hosek, J.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:4EXCZ
Date:Jul 15, 2012
Words:4459
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