Andrographolide interferes with binding of nuclear factor- κ B to DNA in HL-60-derived neutrophilic cells (original) (raw)
Related papers
The Journal of Immunology, 2004
NF-B is a central transcriptional factor and a pleiotropic regulator of many genes involved in immunological responses. During the screening of a plant extract library of traditional Chinese herbal medicines, we found that NF-B activity was potently inhibited by andrographolide (Andro), an abundant component of the plant Andrographis that has been commonly used as a folk remedy for alleviation of inflammatory disorders in Asia for millennia. Mechanistically, it formed a covalent adduct with reduced cysteine (62) of p50, thus blocking the binding of NF-B oligonucleotide to nuclear proteins. Andro suppressed the activation of NF-B in stimulated endothelial cells, which reduced the expression of cell adhesion molecule E-selectin and prevented E-selectinmediated leukocyte adhesion under flow. It also abrogated the cytokine-and endotoxin-induced peritoneal deposition of neutrophils, attenuated septic shock, and prevented allergic lung inflammation in vivo. Notably, it had no suppressive effect on IB␣ degradation, p50 and p65 nuclear translocation, or cell growth rates. Our results thus reveal a unique pharmacological mechanism of Andro's protective anti-inflammatory actions.
Journal of Ethnopharmacology, 2011
Ethnopharmacological significance: Inflammation is involved in numerous diseases, such as chronic inflammatory disease and cancer. Many plant products exhibit useful biological activities, including antifungal, antibacterial, and anti-inflammatory actions. Aim of study: However, our understanding of the anti-inflammatory effects of andrographolide is limited. Materials and methods: We use lipopolysaccharide (LPS)-stimulated macrophages as a model of inflammation to investigate the anti-inflammatory effects of andrographolide, which contains polyphenolic structures. Results: We found that andrographolide exhibited a potent anti-inflammatory effect. In this study, we investigated the inhibitory effects of andrographolide on the induction of nitric oxide synthase (NOS) and cyclooxygenase-2 (COX-2) as well as their respective downstream products, NO and PGE2, in RAW264.7 cells treated with LPS. Treatment with andrographolide also reduced nuclear factor-B (NF-B) and activation protein-1 (AP-1) DNA-binding activity. Western blot analysis showed that andrographolide significantly inhibited the phosphorylation of signal transducer and activator of transcription-3 (STAT3) and the protein expression of CCAAT/enhancer-binding protein ␦ (C/EBP␦). We also found that andrographolide suppressed LPS-induced suppressor of cytokine signalling 1 and 3 (SOCS1 and 3) mRNA expression, which, in turn, inhibited apoptosis signalling and mitochondria membrane potential activation. Our results demonstrate that andrographolide downregulates inflammatory iNOS and COX-2 gene expression by inhibiting the activation of NF-B and STAT3 by interfering with the expression of SOCS1 and SOCS3 signalling. Conclusion: Therefore, andrographolide exerts a potent anti-inflammatory effect and could potentially be developed as a useful agent for the chemoprevention of cancer or inflammatory diseases.
Andrographolide reduces IL2 production in T-cells by interfering with NFAT and MAPK activation
European Journal of Pharmacology, 2009
The nuclear factor of activated Tcells (NFAT) is a transcription factor essential for cytokine production during T-cell activation and is the target of several immunosuppressive drugs. Andrographolide is a diterpenic labdane that possesses anti-inflammatory and immunomodulatory effects. Several studies propose that andrographolide can reduce the immune response through inhibition of the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) such as extracellular signal regulated kinase 1/2 (ERK1/2) pathways. Moreover, andrographolide reduces IFN-γ and IL-2 production induced by concanavalin A in murine T-cell. Nevertheless, the mechanisms involved in the decrease of cytokine production are unknown. In the present study, we determined that andrographolide reduced IL-2 production in Jurkat cells stimulated with phorbol myristate acetate and ionomycin (PMA/Ionomycin). We then showed that andrographolide reduced NFAT luciferase activity and interfered with its nuclear distribution, with these effects being linked to an increase in c-jun-N-terminal kinase (JNK) phosphorylation. Additionally, reduction of NF-κB activity in Jurkat cells treated with andrographolide was observed. Using Western blotting, we demonstrated that andrographolide decreased ERK1 and ERK5 phosphorylation induced by anti-CD3 or PMA/Ionomycin. Andrographolide did not affect cell viability at concentration of 10 and 50 μM; however, our results suggest that andrographolide increase early apoptosis at 100 μM. We concluded that andrographolide can exert immunomodulatory effects by interfering with NFAT activation and ERK1 and ERK5 phosphorylation in T-cells.
Andrographolide a New Potential Drug for the Long Term Treatment of Rheumatoid Arthritis Disease
InTech eBooks, 2013
Andrographis paniculata, (Burm. f.) Wall. ex Nees, a herbaceous plant belonging to the Family Acanthaceae, is one of the most commonly used medicinal plants in the traditional systems of Unani and Ayurvedic medicines. It grows in hedge rows throughout the plains of India and is also cultivated in gardens. It also grows in many other Asian countries and is used as a traditional herbal medicine in China, Hong Kong, the Philippines, Malaysia, Indonesia, and Thailand. It is an annual plant of 1-3 ft high, also known as the "king of bitters", being the aerial parts most commonly used. A. paniculata have shown a broad range of pharmacological effects such as inhibition of replication of the HIV virus, prevention of common cold, and antimalarial, antidiarrheal, antibacterial, antihyperglycemic effects, suppression of various cancer cells, and principally anti-inflammatory properties. Andrographolide is the major labdane diterpenoid isolated from A. paniculata and exhibits anti-inflammatory and anticancer activities, either in vitro or in vivo experimental models of inflammation and cancer. Several immunomodulatory responses of andrographolide have been observed in in vitro studies, such as reduction of iNOS, COX-2, NO, PGE2, TNF-alpha and IL-12 in macrophages and microglia. In neutrophils is able to reduce the radical oxygen species production, and Mac-1, IL-8 and COX-2 expression. In T cells, andrographolide inhibits the expression of IL-2, IFNγ and IL-6, reducing the humoral and cellular adaptive immune response. Andrographolide was able to reduce the dendritic cells maturation and their ability to present antigens to T cells. Andrographolide administered in rodents reduced the Th2 cytokine IL-4, IL-5, IL-13 and serum immunoglobulin in an ovalbumin induced asthma model. A reduction of T cells response also has been observed in experimental autoimmune encephalomyelitis and systemic lupus erythematosus mouse model. Several of immunomodulatory responses have been associated to the inhibition of Nuclear Factor-κB
Journal of Biological Chemistry, 2010
Recent studies have demonstrated that transcription factor nuclear factor (NF)-B inhibition may contribute to the protective anti-inflammatory actions of andrographolide, an abundant component of plants of the genus Andrographis. However, the precise mechanism by which andrographolide inhibits NF-B signaling remains unclear. We thus investigated the mechanism involved in andrographolide suppression of NF-B signaling in rat vascular smooth muscle cells (VSMCs) exposed to proinflammatory stimuli, LPS, and IFN-␥. Andrographolide was shown to suppress LPS/IFN-␥induced inducible nitric-oxide synthase and matrix metalloprotease 9 expression in rat VSMCs. Andrographolide also inhibited LPS/IFN-␥-induced p65 nuclear translocation, DNA binding activity, p65 Ser 536 phosphorylation, and NF-B reporter activity. However, IKK phosphorylation and downstream inhibitory B␣ phosphorylation and degradation were not altered by the presence of andrographolide in LPS/IFN-␥stimulated VSMCs. These andrographolide inhibitory actions could be prevented by selective inhibition of neutral sphingomyelinase and protein phosphatase 2A (PP2A). Furthermore, andrographolide was demonstrated to increase ceramide formation and PP2A activity in VSMCs and to inhibit neointimal formation in rat carotid injury models. These results suggest that andrographolide caused neutral sphingomyelinase-mediated ceramide formation and PP2A activation to dephosphorylate p65 Ser 536 , leading to NF-B inactivation and subsequent inducible nitric-oxide synthase down-regulation in rat VSMCs stimulated by LPS and IFN-␥.
American Journal of Respiratory and Critical Care Medicine, 2009
Rationale: Persistent activation of nuclear factor (NF)-kB has been associated with the development of asthma. Andrographolide, the principal active component of the medicinal plant Andrographis paniculata, has been shown to inhibit NF-kB activity. Objectives: We hypothesized that andrographolide may attenuate allergic asthma via inhibition of the NF-kB signaling pathway. Methods: BALB/c mice sensitized and challenged with ovalbumin (OVA) developed airway inflammation. Bronchoalveolar lavage fluid was assessed for total and differential cell counts, and cytokine and chemokine levels. Serum IgE levels were also determined. Lung tissues were examined for cell infiltration and mucus hypersecretion, and the expression of inflammatory biomarkers. Airway hyperresponsiveness was monitored by direct airway resistance analysis. Measurements and Main Results: Andrographolide dose-dependently inhibited OVA-induced increases in total cell count, eosinophil count, and IL-4, IL-5, and IL-13 levels recovered in bronchoalveolar lavage fluid, and reduced serum level of OVA-specific IgE. It attenuated OVA-induced lung tissue eosinophilia and airway mucus production, mRNA expression of E-selectin, chitinases, Muc5ac, and inducible nitric oxide synthase in lung tissues, and airway hyperresponsiveness to methacholine. In normal human bronchial epithelial cells, andrographolide blocked tumor necrosis factor-a-induced phosphorylation of inhibitory kB kinase-b, and downstream inhibitory kBa degradation, p65 subunit of NF-kB phosphorylation, and p65 nuclear translocation and DNA-binding activity. Similarly, andrographolide blocked p65 nuclear translocation and DNA-binding activity in the nuclear extracts from lung tissues of OVA-challenged mice. Conclusions: Our findings implicate a potential therapeutic value of andrographolide in the treatment of asthma and it may act by inhibiting the NF-kB pathway at the level of inhibitory kB kinase-b activation.
Andrographolide Modulate some Toll-like Receptors and Cytokines Expressions in HL-60 Cell Line
Pharmacy & Pharmacology International Journal
Andrographolide, a labdane diterpenoid, is quantitatively the major bioactive secondary metabolite of Andrographis paniculata, which is now considered to be a promising therapeutic lead for prevention and cure of inflammatory disorders. Although involvements of Toll-like receptors (TLR) and diverse cytokines have been implicated in its modes of actions, as yet no reports on its effects on expressions of TLRs have appeared. Observations reported in this communication reveal that a non-cytotoxic concentration of andrographolide (10 µM) completely suppresses TLR-7 and TLR-8 expressions in HL-60 cells and has no effects on TLR-3 expressions in the cell line. Observed effects of this concentration of andrographolide on the expressions of three quantified cytokines (TNF-α, IL-1β and IL-10) in HL-60 cells were not as pronounced as its suppressing effects on the two TLR expressions. These observations indicate that modulation of TLR-7 and TLR-8 mediated inflammatory and anti-inflammatory cytokines expression are involved in the modes of actions of andrographolide.
TheScientificWorldJournal, 2014
Critical vascular inflammation leads to vascular dysfunction and cardiovascular diseases, including abdominal aortic aneurysms, hypertension, and atherosclerosis. Andrographolide is the most active and critical constituent isolated from the leaves of Andrographis paniculata, a herbal medicine widely used for treating anti-inflammation in Asia. In this study, we investigated the mechanisms of the inhibitory effects of andrographolide in vascular smooth muscle cells (VSMCs) exposed to a proinflammatory stimulus, tumor necrosis factor-α (TNF-α). Treating TNF-α-stimulated VSMCs with andrographolide suppressed the expression of inducible nitric oxide synthase in a concentration-dependent manner. A reduction in TNF-α-induced c-Jun N-terminal kinase (JNK), Akt, and p65 phosphorylation was observed in andrographolide-treated VSMCs. However, andrographolide affected neither IκBα degradation nor p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2 phosphorylation ...
Evidence-Based Complementary and Alternative Medicine, 2013
Andrographolide (AG) is an abundant component of plants of the genusAndrographisand has a number of beneficial properties including neuroprotective, anticancer, anti-inflammatory, and antidiabetic effects. Despite numerous pharmacological studies, the precise mechanism of AG is still ambiguous. Thus, in the present study, we investigated the molecular mechanisms of AG and its target proteins as they pertain to anti-inflammatory responses. AG suppressed the production of nitric oxide (NO) and prostaglandin E2(PGE2), as well as the mRNA abundance of inducible NO synthase (iNOS), tumor necrosis factor-alpha (TNF-α), cyclooxygenase (COX)-2, and interferon-beta (IFN-β) in a dose-dependent manner in both lipopolysaccharide- (LPS-) activated RAW264.7 cells and peritoneal macrophages. AG also substantially ameliorated the symptoms of LPS-induced hepatitis and EtOH/HCl-induced gastritis in mice. Based on the results of luciferase reporter gene assays, kinase assays, and measurement of nuclea...