Viscum album Exerts Anti-Inflammatory Effect by Selectively Inhibiting Cytokine-Induced Expression of Cyclooxygenase-2

Viscum album (VA) preparations are extensively used as complementary therapy in cancer and are shown to exert anti-tumor activities which involve the cytotoxic properties, induction of apoptosis, inhibition of angiogenesis and several other immunomodulatory mechanisms. In addition to their application in cancer therapy, VA preparations have also been successfully utilized in the treatment of several inflammatory pathologies. Owing to the intricate association of inflammation and cancer and in view of the fact that several anti-tumor phytotherapeutics also exert a potent anti-inflammatory effect, we hypothesized that VA exerts an anti-inflammatory effect that is responsible for its therapeutic benefit. Since, inflammatory cytokine-induced cyclo-oxygenase-2 (COX-2) and prostaglandin E2 (PGE2) play a critical role in the pathogenesis of inflammatory diseases, we investigated the anti-inflammatory effect of VA on regulation of cyclo-oxygenase expression and PGE2 biosynthesis by using human lung adenocarcinoma cells (A549 cells) as a model. A549 cells were stimulated with IL-1β and treated with VA preparation (VA Qu Spez) for 18 hours. PGE2 was analysed in the culture supernatants by enzyme immunoassay. Expression of COX-2 and COX-1 proteins was analyzed by immunoblotting and the expression of COX-2 mRNA was assessed by semi-quantitative RT-PCR. We found that VA Qu Spez inhibit the secretion of IL-1β-induced PGE2 in a dose-dependent manner. Further, we also show that this inhibitory action was associated with a reduced expression of COX-2 without modulating the COX-1 expression. Together these results demonstrate a novel anti-inflammatory mechanism of action of VA preparations wherein VA exerts an anti-inflammatory effect by inhibiting cytokine-induced PGE2 via selective inhibition of COX-2.

[1]  T. Kwon,et al.  Withaferin A down-regulates lipopolysaccharide-induced cyclooxygenase-2 expression and PGE2 production through the inhibition of STAT1/3 activation in microglial cells. , 2011, International immunopharmacology.

[2]  S. Kaveri,et al.  Intravenous immunoglobulin therapy in rheumatic diseases , 2011, Nature Reviews Rheumatology.

[3]  J. Hoheisel,et al.  Anti-inflammatory and anti-cancer activities of essential oils and their biological constituents. , 2011, International journal of clinical pharmacology and therapeutics.

[4]  Hyung Gyun Kim,et al.  Anthocyanins from purple sweet potato attenuate dimethylnitrosamine-induced liver injury in rats by inducing Nrf2-mediated antioxidant enzymes and reducing COX-2 and iNOS expression. , 2011, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[5]  G. Kuttan,et al.  Evaluation of the Anti-inflammatory and Anti-tumor Effect of Ipomoea obscura (L) and Its Mode of Action Through the Inhibition of Pro Inflammatory Cytokines, Nitric Oxide and COX-2 , 2011, Inflammation.

[6]  M. Diederich,et al.  Targeting COX-2 expression by natural compounds: a promising alternative strategy to synthetic COX-2 inhibitors for cancer chemoprevention and therapy. , 2010, Biochemical pharmacology.

[7]  M. van Meurs,et al.  Angiopoietin-1 Treatment Reduces Inflammation but Does Not Prevent Ventilator-Induced Lung Injury , 2010, PloS one.

[8]  N. Câmara,et al.  Induction of Heme Oxygenase-1 Can Halt and Even Reverse Renal Tubule-Interstitial Fibrosis , 2010, PloS one.

[9]  U. Göbel,et al.  Anti-Inflammatory Effects of Resveratrol, Curcumin and Simvastatin in Acute Small Intestinal Inflammation , 2010, PloS one.

[10]  M. A. Mohd,et al.  In Vitro and In Vivo Anti-Inflammatory Activity of 17-O-Acetylacuminolide through the Inhibition of Cytokines, NF-κB Translocation and IKKβ Activity , 2010, PloS one.

[11]  V. Gerber,et al.  Treatment of clinically diagnosed equine sarcoid with a mistletoe extract (Viscum album austriacus). , 2010, Journal of veterinary internal medicine.

[12]  Young In Park,et al.  Anti-inflammatory activity of bark of Dioscorea batatas DECNE through the inhibition of iNOS and COX-2 expressions in RAW264.7 cells via NF-κB and ERK1/2 inactivation. , 2010, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[13]  G. Davies,et al.  Neutralisation of Interleukin-13 in Mice Prevents Airway Pathology Caused by Chronic Exposure to House Dust Mite , 2010, PloS one.

[14]  S. Kaveri,et al.  Basophils and nephritis in lupus. , 2010, The New England journal of medicine.

[15]  D. Zeldin,et al.  Pharmacologic Inhibition of COX-1 and COX-2 in Influenza A Viral Infection in Mice , 2010, PloS one.

[16]  H. Kiene,et al.  Review Article: Influence of Viscum album L (European Mistletoe) Extracts on Quality of Life in Cancer Patients: A Systematic Review of Controlled Clinical Studies , 2010, Integrative cancer therapies.

[17]  R. Medzhitov.  Inflammation 2010: New Adventures of an Old Flame , 2010, Cell.

[18]  S. Kaveri,et al.  Basophils as antigen presenting cells. , 2010, Trends in immunology.

[19]  G. Cravotto,et al.  Phytotherapeutics: an evaluation of the potential of 1000 plants , 2010, Journal of clinical pharmacy and therapeutics.

[20]  J. Bayry.  Immunology: TL1A in the inflammatory network in autoimmune diseases , 2010, Nature Reviews Rheumatology.

[21]  M. Carnero,et al.  Overproduction of cyclo-oxygenase-2 (COX-2) is involved in the resistance to apoptosis in vascular smooth muscle cells from diabetic patients: a link between inflammation and apoptosis , 2010, Diabetologia.

[22]  B. Aggarwal,et al.  Curcumin sensitizes human colorectal cancer to capecitabine by modulation of cyclin D1, COX‐2, MMP‐9, VEGF and CXCR4 expression in an orthotopic mouse model , 2009, International journal of cancer.

[23]  A. Pozzi,et al.  Regulation of endothelial cell functions by basement membrane‐ and arachidonic acid‐derived products , 2009, Wiley interdisciplinary reviews. Systems biology and medicine.

[24]  Jagadeesh Bayry,et al.  Novel cellular and molecular mechanisms of induction of immune responses by aluminum adjuvants. , 2009, Trends in pharmacological sciences.

[25]  S. Kaveri,et al.  Surveillance of antigen-presenting cells by CD4+ CD25+ regulatory T cells in autoimmunity: immunopathogenesis and therapeutic implications. , 2009, The American journal of pathology.

[26]  J. Bayry.  Autoimmunity: CTLA-4: a key protein in autoimmunity , 2009, Nature Reviews Rheumatology.

[27]  Yasmin Anum Mohd Yusof,et al.  Ginger Extract (Zingiber Officinale) has Anti-Cancer and Anti-Inflammatory Effects on Ethionine-Induced Hepatoma Rats , 2008, Clinics.

[28]  R. Medzhitov.  Origin and physiological roles of inflammation , 2008, Nature.

[29]  K. Bae,et al.  Anti-inflammatory activity of 4-methoxyhonokiol is a function of the inhibition of iNOS and COX-2 expression in RAW 264.7 macrophages via NF-kappaB, JNK and p38 MAPK inactivation. , 2008, European journal of pharmacology.

[30]  Anup A. Kale,et al.  Cancer phytotherapeutics: role for flavonoids at the cellular level , 2008, Phytotherapy research : PTR.

[31]  Alain Friboulet,et al.  Induction of maturation and activation of human dendritic cells: A mechanism underlying the beneficial effect of Viscum album as complimentary therapy in cancer , 2008, BMC Cancer.

[32]  Peter Libby,et al.  Inflammatory mechanisms: the molecular basis of inflammation and disease. , 2007, Nutrition reviews.

[33]  S. Kaveri,et al.  Rescuing CD4+CD25+ regulatory T-cell functions in rheumatoid arthritis by cytokine-targeted monoclonal antibody therapy. , 2007, Drug discovery today.

[34]  A. C. Williams,et al.  Corrigendum to “Mediators of PGE2 synthesis and signalling downstream of COX-2 represent potential targets for the prevention/treatment of colorectal cancer” [Biochim. Biophys. Acta 1766 (2006) 104–119] , 2007 .

[35]  K. Urech,et al.  Viscotoxins, Mistletoe Lectins and their Isoforms in Mistletoe (Viscum album L.) Extracts Iscador , 2006, Arzneimittelforschung.

[36]  B. Aggarwal,et al.  Curcumin down regulates smokeless tobacco-induced NF-kappaB activation and COX-2 expression in human oral premalignant and cancer cells. , 2006, Toxicology.

[37]  S. Kaveri,et al.  Interleukin-12 is associated with the in vivo anti-tumor effect of mistletoe extracts in B16 mouse melanoma. , 2006, Cancer letters.

[38]  A. C. Williams,et al.  Mediators of PGE2 synthesis and signalling downstream of COX-2 represent potential targets for the prevention/treatment of colorectal cancer. , 2006, Biochimica et biophysica acta.

[39]  L. Heinzerling,et al.  Immunologic Effector Mechanisms of a Standardized Mistletoe Extract on the Function of Human Monocytes and Lymphocytes in vitro, ex vivo, and in vivo , 2006, Journal of Clinical Immunology.

[40]  M. Radenković,et al.  Neurophysiological effects of mistletoe (Viscum album L.) on isolated rat intestines , 2006, Phytotherapy research : PTR.

[41]  E. Kuepeli,et al.  Anti-Inflammatory and Antinociceptive Activity of Flavonoids Isolated from Viscum album ssp. album , 2006, Zeitschrift fur Naturforschung. C, Journal of biosciences.

[42]  Chi-Tang Ho,et al.  Modulation of arachidonic acid metabolism and nitric oxide synthesis by garcinol and its derivatives. , 2006, Carcinogenesis.

[43]  J. van Hattum,et al.  Exploratory study on the effects of treatment with two mistletoe preparations on chronic hepatitis C. , 2011, Arzneimittel-Forschung.

[44]  W. Hatzmann,et al.  Prevention of surgery-induced suppression of granulocyte function by intravenous application of a fermented extract from Viscum album L. in breast cancer patients. , 2005, Anticancer research.

[45]  G. Pastelín,et al.  Vasodilator activity of the aqueous extract of Viscum album. , 2005, Fitoterapia.

[46]  J. Beuth,et al.  Influence of complementary Viscum album (Iscador) administration on microcirculation and immune system of ear, nose and throat carcinoma patients treated with radiation and chemotherapy. , 2005, Anticancer research.

[47]  Y. Surh,et al.  Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular targets for chemoprevention. , 2004, Biochemical pharmacology.

[48]  V. Lavastre,et al.  Anti‐inflammatory effect of Viscum album agglutinin‐I (VAA‐I): induction of apoptosis in activated neutrophils and inhibition of lipopolysaccharide‐induced neutrophilic inflammation in vivo , 2004, Clinical and experimental immunology.

[49]  B. Schneider,et al.  [Efficacy and safety of long-term complementary treatment with standardized European mistletoe extract (Viscum album L.) in addition to the conventional adjuvant oncologic therapy in patients with primary non-metastasized mammary carcinoma. Results of a multi-center, comparative, epidemiological coh , 2004, Arzneimittel-Forschung.

[50]  S. Kaveri,et al.  Comparative Study of the Sensitivity of Lymphoblastoid and Transformed Monocytic Cell Lines to the Cytotoxic Effects of Viscum album Extracts of Different Origin , 2003, Chemotherapy.

[51]  F. Daschner,et al.  Influence of Mistletoe (Viscum album) Extracts on Phagocytosis/Burst Activity of Human Phagocytes , 2003, European Journal of Clinical Microbiology and Infectious Diseases.

[52]  N. Arda,et al.  Antiviral potency of mistletoe (Viscum album ssp. album) extracts against human parainfluenza virus type 2 in Vero cells , 2003, Phytotherapy research : PTR.

[53]  H. Rosenkranz,et al.  SAR: flavonoids and COX-2 inhibition. , 2003, Oncology research.

[54]  A. Büssing,et al.  Stimulation of the maturation of dendritic cells in vitro by a fermented mistletoe extract. , 2002, Anticancer research.

[55]  S. Kaveri,et al.  Induction of Apoptosis of Endothelial Cells by Viscum album: A Role for Anti-Tumoral Properties of Mistletoe Lectins , 2002, Molecular medicine.

[56]  S. Chrubasik,et al.  Treatment of low back pain with a herbal or synthetic anti-rheumatic: a randomized controlled study. Willow bark extract for low back pain. , 2001, Rheumatology.

[57]  S. Kaveri,et al.  Variable Sensitivity of Lymphoblastoid Cells to Apoptosis Induced by Viscum album Qu FrF, a Therapeutic Preparation of Mistletoe Lectin , 2001, Chemotherapy.

[58]  T. Kang,et al.  Cellular and humoral adjuvant activity of lectins isolated from Korean mistletoe (Viscum album colaratum). , 2001, International immunopharmacology.

[59]  C. Kramers,et al.  Iscador Qu for chronic hepatitis C: an exploratory study. , 2001, Complementary therapies in medicine.

[60]  J. Meyer-Kirchrath,et al.  Cyclooxygenase-2 inhibition and side-effects of non-steroidal anti-inflammatory drugs in the gastrointestinal tract. , 2000, Current medicinal chemistry.

[61]  A. Büssing,et al.  Intracellular expression of IL-4 and inhibition of IFN-gamma by extracts from European mistletoe is related to induction of apoptosis. , 2000, Anticancer research.

[62]  A. Büssing,et al.  Toxic proteins from European mistletoe (Viscum album L.): increase of intracellular IL-4 but decrease of IFN-gamma in apoptotic cells. , 2000, Anticancer research.

[63]  A. Büssing,et al.  Apoptosis-inducing properties of Viscum album L. extracts from different host trees, correlate with their content of toxic mistletoe lectins. , 1999, Anticancer research.

[64]  E. Kaegi.  Unconventional therapies for cancer: 3. Iscador , 1998 .

[65]  E. Kaegi.  Unconventional therapies for cancer: 1. Essiac. , 1998 .

[66]  E. Kaegi.  Unconventional therapies for cancer: 3. Iscador. Task Force on Alternative Therapies of the Canadian Breast Cancer Research Initiative. , 1998, CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne.

[67]  R. Saller,et al.  A plant ribosome inactivating protein, Viscum album Agglutinin-I (VAA-I) induces cytokine gene expression and apoptosis in cultures of peripheral blood mononuclear cells , 1997 .

[68]  A. Morrison,et al.  Antioxidants Inhibit Interleukin-1-induced Cyclooxygenase and Nitric-oxide Synthase Expression in Rat Mesangial Cells , 1996, The Journal of Biological Chemistry.

[69]  G. Engelhardt,et al.  Distinct isoforms (COX‐1 and COX‐2) of cyclooxygenase: possible physiological and therapeutic implications , 1996, Fundamental & clinical pharmacology.

[70]  J. Vane,et al.  Mechanism of action of anti-inflammatory drugs. , 1996, Scandinavian journal of rheumatology. Supplement.

[71]  R. Herrmann,et al.  A plant lectin derived from Viscum album induces cytokine gene expression and protein production in cultures of human peripheral blood mononuclear cells. , 1995, Natural immunity.

[72]  T. Khwaja,et al.  Recent studies on the anticancer activities of mistletoe (Viscum album) and its alkaloids. , 1986, Oncology.

[73]  H. Thaler,et al.  Prostaglandins in breast cancer: relationship to disease stage and hormone status. , 1983, British Journal of Cancer.

[74]  B. Ramot,et al.  Monocyte PGE2 secretion in Hodgkin's disease and its relation to decreased cellular immunity. , 1983, Clinical and experimental immunology.

[75]  F. Stirpe,et al.  Isolation and characterization of viscumin, a toxic lectin from Viscum album L. (mistletoe). , 1982, The Journal of biological chemistry.

[76]  H. Franz,et al.  Isolation and properties of three lectins from mistletoe (Viscum album L.). , 1981, The Biochemical journal.

[77]  R. Winkelmann,et al.  Prostaglandin activity in human cutaneous inflammation: detection by radioimmunoassay. , 1973, Prostaglandins.