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Inhibitory Effect of Berberine on Interleukin-2 Secretion from PHA-Treated Lymphocytic Jurkat Cells

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Inhibitory Effect of Berberine on Interleukin-2 Secretion from PHA-Treated Lymphocytic Jurkat Cells International Immunopharmacology 66 (2019) 267–273 Contents lists available at ScienceDirect International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp Inhibitory effect of berberine on interleukin-2 secretion from PHA-treated lymphocytic Jurkat cells T Sindy Hua,b,1, Chien-Wei Chenc,1, Szu-Tah Chend, Ke-Hung Tsuie,f, Tswen-Kei Tangg, ⁎ Hao-Tsai Chengh,i, Guey-Shyang Hwanga,j,k, Ju-Wen Yuc, Yi-Chieh Lic, Paulus S. Wangl,m,n, , ⁎⁎ Shyi-Wu Wanga,c, a Aesthetic Medical Center, Department of Dermatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan, Republic of China b Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China c Department of Physiology and Pharmacology, Chang Gung University, Taoyuan, Taiwan, Republic of China d Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan, Republic of China e Department of Urology, Division of Geriatric Urology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan, Republic of China f Bioinformation Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, Republic of China g Department of Nursing, National Quemoy University, Kinmen County, Taiwan, Republic of China h Division of Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan, Republic of China i Graduate Institute of Clinical Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China j Department of Nursing, Chang Gung University of Science and Technology, Taoyuan, Taiwan, Republic of China k Department of Nutrition and Health Sciences, Chang Gung University of Science and Technology, Taoyuan, Taiwan, Republic of China l Medical Center of Aging Research, China Medical University Hospital, Taichung, Taiwan, Republic of China m Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan, Republic of China n Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China ARTICLE INFO ABSTRACT Keywords: Berberine is an isoquinoline alkaloid isolated from herb plants, such as Cortex phellodendri (Huangbai) and Berberine Rhizoma coptidis (Huanglian). Huanglian and Huangbai have been used as “heat-removing” agents. In addition, Cell cycle berberine has been reported to exert anti-inflammatory effect both in vivo and in vitro, where mitogen-activated Cyclooxygenase-2 protein kinase (MAPK) and cyclooxygenase-2 (COX-2) expressions are critically implicated. We herein tested the Jurkat cells hypothesis that berberine exerts an anti-inflammatory effect through MAPK and COX-2 signaling pathway in T- Interleukin-2 cell acute lymphoblastic leukemia (T-ALL). In Jurkat cells, we found that PHA exposure caused elevation on p38 interleukin-2 (IL-2) production in a time-dependent manner. PHA-stimulated reactions were steeply suppressed by berberine, such as IL-2 mRNA expression and protein secretion. However, berberine did not exert any cy- totoxic effect at doses of 40 μg/ml. In addition, the possible molecular mechanism of anti-inflammation effect of berberine could be the inhibition of PHA-evoked phosphorylation of p38, since c-Jun N-terminal kinases (JNK) and extracellular signal-regulated kinase (ERK) expressions did not alter. Consistent with above results, ber- berine inhibition on PHA-induced IL-2 secretion could be reversed by treatment of SB203580, a specific inhibitor of p38-MAPK. Interestingly, upregulation of PHA-induced COX-2 expression was also observed following ber- berine treatment of Jurkat cells. Furthermore, flow cytometry analysis showed berberine-induced cell cycle arrest at G1 phase after PHA stimulation and decreased percentage of G2/M phase. In conclusion, our study demonstrated that the anti-inflammatory effect of berberine largely potentially results from its ability to at- tenuate p38 MAPK expression, and does not exclude a positive action of berberine on cell cycle arrest. These results provide an innovative medicine strategy to against or treat T-ALL patients. ⁎ Correspondence to: Medical Center of Aging Research, China Medical University Hospital, Taichung 40402, Taiwan, Republic of China. ⁎⁎ Correspondence to: S.-W. Wang, Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan, Republic of China. E-mail addresses: [email protected] (P.S. Wang), [email protected] (S.-W. Wang). 1 These authors contributed equally to this work and should be considered co-first authors. https://doi.org/10.1016/j.intimp.2018.11.020 Received 4 October 2018; Received in revised form 13 November 2018; Accepted 14 November 2018 Available online 28 November 2018 1567-5769/ © 2018 Published by Elsevier B.V. S. Hu et al. International Immunopharmacology 66 (2019) 267–273 1. Introduction Signaling (Beverly, MA, USA). The lactate dehydrogenase (LDH) assay kit was purchased from Abcam (Cambridge, MA, USA). Chemical re- The main feature of T-cell acute lymphoblastic leukemia (T-ALL) is agents (L-glutamine, sodium pyruvate, sodium bicarbonate, HEPES) an aggressive hematological cancer that arises from T-cell progenitors. were purchased from Sigma-Aldrich (St. Louis, MO, USA). The fol- Clinical studies have shown that ALL patients are accompanied with lowing materials were ordered from the companies indicated: ber- strong inflammatory state, owing to elevated cytokine levels in circu- berine, phytohemagglutinin (PHA, Sigma-Aldrich), cell culture media lation system [1,2]. Intensified chemotherapy is the most common (RPMI-1640) and fetal bovine serum (Gibco, Green Island, NY, USA). treatment schedules for T-ALL, but often combined with considerable side effects [3,4]. Despite the progress of chemotherapy in recent 2.2. Cell culture years, > 50% of adult patients with T-ALL still appear resistance to therapy and relapsed/refractory phenomenon [5], and the 5-year sur- T-ALL Jurkat cells were routinely cultured in RPMI-1640 medium vival rate is as low as 45% for adult T-ALL patients [6,7]. T-ALL has supplemented with 10% heat-inactivated fetal bovine serum, 1 mM therefore been rated the most challenging issue of malignant tumor, sodium pyruvate, 2 mM L-glutamine, 1.5 g/L sodium bicarbonate, 4.5 g/ especially with respect to therapy. Hence, to find new effective thera- L glucose, and 10 mM HEPES at 37 °C in a humidified chamber con- pies, especially herb drugs, for T-ALL patients are still a goal for re- taining 5% CO2. T-ALL Jurkat cells were grown in 24-well culture plates searchers. at a density of 1 × 106 cells/ml. This study evaluated the inflammatory Berberine, a quaternary ammonium of isoquinoline alkaloids, is properties in the presence (treatment group) and absence (placebo purified from medicinal plants, such as Rhizoma coptidis (Huanglian) group) of berberine in T-ALL Jurkat cells. As illustrated in the text and and Hydrastis canadensis (goldenseal) [8]. Berberine has traditionally figure legends, cells were cultured in berberine and PHA at different been used as herbal medicine in Asia, including China. Previous studies time intervals depending on subsequent measurements. showed that berberine displays potential anti-inflammation activities by suppressing mitogen-activated protein kinase (MAPK) and pro- 2.3. IL-2 ELISA assay moting macrophage apoptosis [9]. Moreover, with respect to cancer biology, MAPK signaling pathway plays a critical role in cell growth/ Determination of IL-2 level was done following the method de- proliferation process. There is a growing body of evidence supporting scribed previously [20]. Briefly, polystyrene microtiter plates (NUNC, the inhibitory effects of berberine on tumorigenicity of numerous types U16 Maxisorp type, Denmark) were coated with capture antibodies (R& of cancer cells, by attribute of modulating cell growth-associated me- D Systems) at room temperature overnight. The next day, IL-2 standard chanisms, including MAPK signaling pathway [10,11] and apoptosis- and samples were added to the plate wells, incubated at room tem- inducing proteins [12,13]. On the other hand, cyclooxygenase-2 (COX- perature after blocked, and exposed to detection antibody (R&D Sys- 2), an enzyme that catalyzes prostaglandin biosynthesis, is one of the tems) followed by streptavidin horseradish peroxidase enzyme (R&D most common proteins correlated with inflammation and tumorigen- Systems). IL-2 concentrations were measured using a tetra- esis. However, studies on the role of COX-2 expression in cancer biology methylbenzidine substrate and the reaction was ceased with 2 N sul- remain controversial. COX-2 has been shown to have both positive and phuric acid. Finally, absorbance at 450 nm was read on a plate reader negative effects on cell proliferation. Investigators have showed that (BioTek, Winooski, VT, USA). Cytokine standard curves were used to decreased COX-2 is associated with anti-cancer activity in leukemia cell calculate the amount of IL-2 in supernatant samples. The IL-2 ELISA through several mechanisms. It not only promotes cell apoptosis and was established with a detection range from 31.5 to 2000 pg/ml, and cell cycle arrest [14], but attenuates tumor cell blastogenesis as well the intra- and inter-assay coefficients of variation were 10.2% and [14,15]. In contrast, overexpression of COX-2 in osteosarcoma cells 6.4%, respectively. leads to dramatic cell number decrease by 50%–70%, and attenuates proliferation
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