Anti-Inflammatory Compounds of Plant Origin. Part II. Modulation of Pro-Inflammatory Cytokines, Chemokines and Adhesion Molecules

Abstract

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica.

Abbreviations

AP-1:activator protein-1

CCR1:chemokine receptor 1

CINC-1:cytokine-induced neutrophil chemoattractant 1

COX:cyclooxygenase

EGCG:(-)-epigallocatechin gallate

ELAM-1:endothelial-leukocyte adhesion molecule-1

ERK:extracellular signal-regulated kinase

GRO:growth-related oncogene

HUVEC:human umbilical vein endothelial cells

ICAM-1:intercellular adhesion molecule-1

IFN:interferon

IL:interleukin

iNOS:inducible nitric oxide synthase

IRA:the natural interleukin receptor activation

JAK:janus kinase

JNK:c-Jun NH2-terminal kinase

LPS:lipopolysaccharide

MAPK:mitogen-activated protein kinases

MCP:monocyte chemotactic protein

MHC:major histocompatibility complex

MIP:macrophage inflammatory protein

MMP:matrix metalloproteinases

MPO:myeloperoxidase

NF-κBnuclear factor kappa B

NO:nitric oxide

PAF:platelet aggregation factor

PGEE:prostaglandin

PK:protein kinase

PMA/TPA:phorbol myristate acetate

RANTES:regulated upon activation normal T-cell expressed and secreted

TGF-β:transforming growth factor-β

TNFα:tumour necrosis factor

VCAM-1:vascular cell adhesion molecule-1

Key words

Medicinal plants - plant constituents - inflammation - cytokines - chemokines - adhesion molecules

References

• 1 Sacca R, Cuff C A, Ruddle N H. Mediators of inflammation.  Current Opinion in Immunology. 1997;  9 851-7
• 2 Barnes P J. Cytokine modulators as novel therapies for asthma.  Annual Review in Pharmacology and Toxicology. 2002;  42 81-98
• 3 Haddad J J. Cytokines and related receptor-mediated signaling pathways.  Biochemical and Biophysical Communications. 2002;  297 700-13
• 4 Hopkins S J. The pathophysiological role of cytokines.  Legal Medicine. 2003;  5 S45-57
• 5 Dinarello C A. Pro-inflammatory cytokines.  Chest. 2000;  118 503-8
• 6 Opal S M, DePalo V A. Anti-inflammatory cytokines.  Chest. 2000;  117 1162-72
• 7 Kracht M, Saklatvala J. Transcriptional and post-transcriptional control of gene expression in inflammation.  Cytokine. 2002;  20 91-106
• 8 Barnes P J, Karin M. Nuclear factor-κB - a pivotal transcription factor in chronic inflammatory diseases.  The New England Journal of Medicine. 1997;  336 1006-71
• 9 Donaldson L F, Hanley M R, Villabalnca A C. Inducible receptors.  Trends in Pharamcological Sciences. 1997;  18 171-81
• 10 Luster A D. Chemokines - chemotatic cytokines that mediate inflammation.  New England Journal of Medicine. 1998;  338 436-45
• 11 Wong M M, Fish E N. Chemokines: attractive mediators of the immune response.  Seminars in Immunology. 2003;  15 5-14
• 12 D’Ambrosio D, Panina-Bordignon P, Sinigaglia F. Chemokine receptors in inflammation: an overview.  Journal of Immunological Methods. 2003;  273 3-13
• 13 Feldmann M, Brennan F M, Maini R. Cytokines in autoimmune disorders.  Internal Review in Immunology. 1998;  17 217-28
• 14 Proudfoot A EI, Power C A, Rommel C, Wells T NC. Strategies for chemokine antagonists as therapeutics.  Seminars in Immunology. 2003;  15 57-65
• 15 Young P R. Pharmacological modulation of cytokine action and production through signaling pathways.  Cytokine & Growth Factor Reviews. 1998;  9 239-57
• 16 Andreakos E T, Foxwell B M, Brennan F M, Maini R N, Feldmann M. Cytokinies and anti-cytokine biologicals in autoimmunity: present and future.  Cytokine & Growth Factor Reviews. 2002;  13 299-313
• 17 Feldmann M. Development of anti-TNF therapy for rheumatoid arthritis.  Nature Review Immunology. 2002;  2 364-71
• 18 Habtemariam S. Natural inhibitors of tumor necrosis factor-α production, secretion and function.  Planta Medica. 2000;  66 303-13
• 19 Gerritsen M E, Carley W W, Ranges G E, Shen C P, Phan S A, Ligon G F, Perry C A. Flavonoids inhibit cytokine-induced endothelial cell adhesion protein gene expression.  American Journal of Pathology. 1995;  147 278-92
• 20 Middleton E J r. Effect of plant flavonoids on immune and inflammatory cell function.  Advance Experimental Medicine and Biology. 1998;  439 175-82
• 21 Di Carlo G, Mascolo N, Izzo A A, Capasso F. Flavonoids: old and new aspects of a class of natural therapeutic drugs.  Life Sciences. 1999;  65 337-53
• 22 Xagorari A, Papapetropoulos A, Mauromatis A, Economou M, Fotsis T, Roussos C. Luteolin inhibits an endotoxin-stimulated phosphorylation cascade and proinflammatory cytokine production in macrophages.  The Journal of Pharmacology and Experimental Therapeutics. 2001;  296 181-7
• 23 Ueda H, Yamazaki C, Yamazaki M. Luteolin as an anti-inflammatory and anti-allergic constituent of Perilla frutescens .  Biological & Pharmaceutical Bulletin. 2002;  25 1197-202
• 24 Kotanidou A, Xagorari A, Bagli E, Kitsanta P, Fotsis T, Papapetropoulos A, Roussos C. Luteolin reduces lipopolysaccharide-induced lethal toxicity and expression of proinflammatory molecules in mice.  American Journal of Respiratory Critical Care in Medicine. 2002;  1165 818-23
• 25 Das M, Ram A, Ghosh B. Luteolin alleviates bronchoconstriction and airway hyperreactivity in ovalbumin sensitized mice.  Inflammation Research. 2003;  52 101-6
• 26 Manna S K, Mukhopadhyay A, Van N T, Aggrawal B B. Silymarin suppresses TNF-induced activation of NF-κB, c-Jun N-terminal kinase, and apoptosis.  The Journal of Immunology. 1999;  163 6800-9
• 27 Johnson V J, Osuchowski M F, He Q, Sharma R P. Physiological responses to a natural antioxidant flavonoid mixture, silymarin, in BALB/c mice: II. Alterations in thymic differentiation correlate with changes in c-myc gene expression.  Planta Medica. 2002;  68 961-5
• 28 Ishiwa J, Sato T, Mimaki Y, Sashida Y, Yano M, Ito A. A citrus flavonoid, nobiletin, suppresses production and gene expression of matrix metalloproteinase 9/gelatinase B in rabbit synovial fibroblasts.  Journal of Rheumatology. 2000;  27 20-5
• 29 Lin N, Sato T, Takayama Y, Mimaki Y, Sashida Y, Yano M, Ito A. Novel anti-inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts and mouse macrophages.  Biochemical Pharmacology. 2003;  65 2065-71
• 30 Kubo M, Matsuda H, Tanaka M, Kimura Y, Okuda H, Higashino M, Tani T, Namba K, Arichi S. Studies on Scutellariae radix: VII. Anti-arthritic and anti-inflammatory actions of methanolic extract and flavonoids components from Scutellariae radix.  Chemistry Pharmacology Bulletin. 1984;  32 2724-9
• 31 Chen Y -C, Shen S -C, Chen L -G, Lee T J -F, Yang L -L. Wogonin, baicalin, and baicalein inhibition of inducible nitric oxide synthase and cyclooxygenase-2 gene expressions induced by nitric oxide synthase inhibitors and lipopolysaccharide.  Biochemical Pharmacology. 2001;  61 1417-27
• 32 Chiu J H, Lay I S, Su M Y, Chiu H L, Chiu S N, Lui W Y, Wu C W. Tumor necrosis factor-producing activity of wogonin in RAW 264.7 murine macrophage cell line.  Planta Medica. 2002;  68 1036-9
• 33 Li B Q, Fu T, Gong W -H, Dunlop N, Kung H -F, Yan Y, Kang J, Wang J M. The flavonoids baicalin exhibits anti-inflammatory activity by binding to chemokines.  Immunopharmacology. 2000;  49 295-306
• 34 Nakajima T, Imanishi M, Yamamoto K, Cyong J C, Hirai K. Inhibitory effect of baicalein, a flavonoid in Scutellaria Root, on eotaxin production by human dermal fibroblasts.  Planta Medica. 2001;  67 32-5
• 35 Kimura Y, Matsushita N, Yokoi-Hayashi K, Okuda H. Effects of baicalein isolated from Scutellaria baicalensis on adhesion molecule expression induced by thrombin and thrombin receptor agonist peptide in cultured human umbilical vein endothelial cells.  Planta Medica. 2001;  67 331-4
• 36 Sartor L, Pezzato E, Dell’Aica I, Caniato R, Biggin S, Garbisa S. Inhibition of matrix-proteases by polyphenols: chemical insights for anti-inflammatory and anti-invasion drug design.  Biochemical Pharmacology. 2002;  64 229-37
• 37 Krakauer T, Li B Q, Young H A. The flavonoid baicalin inhibits superantigen-induced inflammatory cytokines and chemokines.  FEBS Letters. 2001;  500 52-5
• 38 Shen Y C, Chiou W F, Chou Y C, Chen C F. Mechanisms in mediating the anti-inflammatory effects of baicalin and baicalein in human leukocytes.  European Journal of Pharmacology. 2003;  465 171-81
• 39 Nakamura N, Hayasaka S, Zhang X Y, Nagaki Y, Matsumoto M, Hayasaka Y, Terasawa K. Effects of baicalin, baicalein, and wogonin on interleukin-6 and interleukin-8 expression, and nuclear factor-kappa B binding activities induced by interleukin-1beta in human retinal pigment epithelial cell line.  Experimental Eye Research. 2003;  77 195-202
• 40 Wadsworth T L, McDonald T L, Koop D R. Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced signaling pathways involved in the release of tumor necrosis factor-α.  Biochemical Pharmacology. 2001;  62 963-74
• 41 Manjeet K R, Ghosh B. Quercetin inhibits LPS-induced nitric oxide and tumor necrosis factor-α production in murine macrophages.  International Journal of Immunopharmacology. 1999;  21 435-43
• 42 Wei B L, Lu C M, Tsao L T, Wang J P, Lin C N. In vitro anti-inflammatory effects of quercetin 3-O-methyl ether and other constituents from Rhamnus species.  Planta Medica. 2001;  67 745-47
• 43 Cho J Y, Kim P S, Park J, Yoo E S, Baik K U, Kim Y K, Park M H. Inhibitor of tumor necrosis factor-alpha production in lipopolysaccharide-stimulated RAW264.7 cells from Amorpha fruticosa .  Journal of Ethnopharmacology. 2000;  70 127-33
• 44 Park K Y, Lee S H, Min B K, Lee K S, Choi J S, Chung S R, Min K R, Kim Y. Inhibitory effect of luteolin 4′-O-glucoside from Kummerowia striata and other flavonoids on interleukin-5 bioactivity.  Planta Medica. 1999;  65 457-9
• 45 Okabe S, Suganuma M, Imayoshi Y, Taniguchi S, Yoshida T, Fujiki H. New TNFα releasing inhibitors, geraniin and corilagin, in leaves of Acer nikoense, Megusurino-Ki.  Biological & Pharmaceutical Bulletin. 2001;  10 1145-8
• 46 Jang M K, Sohn D H, Ryu J H. A curcuminoid and sesquiterpenes as inhibitors of macrophage TNF-alpha release from Curcuma zedoaria .  Planta Medica. 2001;  67 550-2
• 47 Kang B Y, Chung S W, Kim T S. Inhibition of interleukin-12 production in lipopolysaccharide-activated mouse macrophages by hypericin, an active component of Hypericum perforatum .  Planta Medica. 2001;  67 364-6
• 48 Bork P M, Bacher S, Schimitz M L, Kaspers U, Heinrich M. Hypericin as a non-antioxidant inhibitor of NF-kappa B.  Planta Medica. 1999;  65 297-300
• 49 Oh G S, Pae H O, Choi B M, Jeong S, Oh H, Oh C S, Rho Y D, Kim D H, Shin M K, Chung H T. Inhibitory effects of the root cortex of Paeonia suffruticosa on interleukin-8 and macrophage chemoattractant protein-1 secretions in U937 cells.  Journal of Ethnopharmacology. 2003;  84 85-9
• 50 Chou T C. Anti-inflammatory and analgesic effects of paeonol in carrageenan-evoked thermal hyperalgesia.  British Journal of Pharmacology. 2003;  139 1146-52
• 51 Cho K J, Yun C H, Packer L, Chung A S. Inhibition mechanisms of bioflavonoids extracted from the bark of Pinus maritima on the expression of proinflammatory cytokines.  Annals of the New York Academy of Science. 2001;  928 141-56
• 52 Bito T, Roy S, Sen C K, Shirakawa T, Gotoh A, Ueda M, Ichihashi M, Packer L. Flavonoids differentially regulate IFN-γ-induced ICAM-1 expression in human keratinocytes: molecular mechanisms of action.  FEBS Letters. 2002;  520 145-52
• 53 Manthey J A, Grohmann K, Montanari A, Ash K, Manthey C L. Polymethoxylated flavones derived from Citrus suppress tumor necrosis factor-α expression by human monocytes.  Journal Natural Products. 1999;  62 441-4
• 54 Hunter M S, Corley D G, Carron C P, Rowold E, Kilpatrick B F, Durley R C. Four new clerodane diterpenes from the leaves of Casearia guianensis which inhibit the interaction of leukocyte function antigen 1 with intercellular adhesion molecule 1.  Journal Natural Products. 1997;  60 894-99
• 55 Ahn K S, Kim J H, Oh S R, Ryu S Y, Lee H K. Inhibitory activity of stilbenes from medicinal plants on the expression of cell adhesion molecules on THP1 cells.  Planta Medica. 2000;  66 641-4
• 56 Tanaka S, Sakata Y, Morimoto K, Tambe Y, Watanabe Y, Honda G, Tabata M, Oshima T, Masuda T, Umezawa T, Shimada M, Nagakura N, Kamisako W, Kashiwada Y, Ikeshiro Y. Influence of natural and synthetic compounds on cell surface expression of cell adhesion molecules, ICAM-1 and VCAM-1.  Planta Medica. 2001;  67 108-13
• 57 Yamazaki R, Hatano H, Aiyama R, Matsuzaki T, Hashimoto S, Yokokura T. Diarylheptanoids suppress expression of leukocyte adhesion molecules on human vascular endothelial cells.  European Journal of Pharmacology. 2000;  404 375-85
• 58 Ashikawa K, Majumdar S, Banerjee S, Bharti A C, Shishodia S, Aggarwal B B. Piceatannol inhibits TNF-induced NF-kappaB activation and NF-kappaB-mediated gene expression through suppression of IkappaB-alpha kinase and p65 phosphorylation.  The Journal of Immunology. 2002;  169 6490-7
• 59 Krakauer T. The polyphenol chlorogenic acid inhibits staphylococcal exotoxin-induced inflammatory cytokines and chemokines.  Immunopharmacology and Immunotoxicology. 2002;  24 113-9
• 60 Jung J H, Ha J Y, Min K R, Shibata F, Nakagawa H, Kang S S, Chang I M, Kim Y. Reynosin from Sassurea lappa as inhibitor on CINC-1 induction in LPS-stimulated NRK-52E cells.  Planta Medica. 1998;  64 54-5
• 61 Tsuda T, Horio F, Osawa T. Cyanidin 3-O-beta-D-glucoside suppresses nitric oxide production during a zymosan treatment in rats.  Journal of Nutrition Sciences Vitaminol (Tokyo). 2002;  48 305-10
• 62 Ishii R, Horie M, Saito K, Arisawa M, Kitanaka S. Inhibition of lipopolysaccharide-induced pro-inflammatory cytokine expression via suppression of nuclear factor-kappaB activation by Mallotus japonicus phloroglucinol derivatives.  Biochimica et Biophysica Acta. 2003;  1620 108-18
• 63 Calixto J B, Otuki M F, Santos A RS. Anti-inflammatory compounds of plant origin. Part I. Action on arachidonic acid pathway, nitric oxide and nuclear factor κ B (NF-κB).  Planta Medica. 2003;  69 973-83
• 64 Natarajan C, Bright J J. Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through Janus Kinase-STAT pathway in T lymphocytes.  The Journal of Immunology. 2002;  169 6506-13
• 65 Liacini A, Sylvester J, Qing Li W, Huang W, Dehnade F, Ahmad M, Zafarullah M. Induction of matrix metalloproteinase-13 gene expression by TNF-alpha is mediated by MAP kinases, AP-1, and NF-kappaB transcription factors in articular chondrocytes.  Experimental Cell Research. 2003;  288 208-17
• 66 Banerjee M, Tripathi L M, Srivastava V M, Puri A, Shukla R. Modulation of inflammatory mediators by ibuprofen and curcumin treatment during chronic inflammation in rat.  Immunopharmacology and Immunotoxicology. 2003;  25 213-24
• 67 Chainani-Wu N. Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa).  The Journal of Alternative & Complementary Medicine. 2003;  9 161-8
• 68 Cheng A L, Hsu C H, Lin J K, Hsu M M, Ho Y F, Shen T S, Ko J Y, Lin J T, Lin B R, Ming-Shiang W, Yu H S, Jee S H, Chen G S, Chen T M, Chen C A, Lai M K, Pu Y S, Pan M H, Wang Y J, Tsai C C, Hsieh C Y. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions.  Anticancer Research. 2001;  21 2895-900
• 69 Aggarwal B B, Kumar A, Bharti A C. Anticancer potential of curcumin: preclinical and clinical studies.  Anticancer Research. 2003;  23 363-98
• 70 Oh S R, Kim D S, Lee I S, Jung K Y, Lee J J, Lee H K. Anticomplementary activity of constituents from the heartwood of Caesalpinia sappan .  Planta Medica. 1998;  64 456-8
• 71 Oh G T, Choi J H, Hong J J, Kim D Y, Lee S B, Kim J R, Lee C H, Hyun B H, Oh S R, Bok S H, Jeong T S. Dietary hematein ameliorates fatty streak lesions in the rabbit by the possible mechanism of reducing VCAM-1 and MCP-1 expression.  Atherosclerosis. 2001;  159 17-26
• 72 Hong J J, Jeong T S, Choi J H, Park J H, Lee K Y, Seo Y J, Oh S R, Oh G T. Hematein inhibits tumor necrotic factor-alpha-induced vascular cell adhesion molecule-1 and NF-kappaB-dependent gene expression in human vascular endothelial cells.  Biochemical and Biophysical Research Communications. 2001;  281 1127-33
• 73 Choi J H, Jeong T S, Kim D Y, Kim Y M, Na H J, Nam K H, Lee S B, Kim H C, Oh S R, Choi Y K, Bok S H, Oh G T. Hematein inhibits atherosclerosis by inhibition of reactive oxygen generation and NF-kappaB-dependent inflammatory mediators in hyperlipidemic mice.  Journal of Cardiovascular Pharmacology. 2003;  42 287-95
• 74 Cho J Y, Park J, Yoo E S, Yoshikawa K, Baik K U, Lee J, Park M H. Inhibitory effect of lignans from the rhizomes of Coptis japonica var. dissecta on tumor necrosis factor-alpha production in lipopolysaccharide-stimulated RAW264.7 cells.  Archive of Pharmacal Research. 1998;  21 12-6
• 75 Cho J Y, Baik K U, Yoo E S, Yoshikawa K, Park M H. In vitro anti-inflammatory effects of neolignan woorenosides from the rhizomes of Coptis japonica .  Journal of Natural Products. 2000;  63 1205-9
• 76 Cho J Y, Park J, Kim P S, Yoo E S, Baik K U, Park M H. Savinin, a lignan from Pterocarpus santalinus inhibits tumor necrosis factor-alpha production and T cell proliferation.  Biological & Pharmaceutical Bulletin. 2001;  24 167-71
• 77 Cho J Y, Kim A R, Park M H. Lignans from the rhizomes of Coptis japonica differentially act as anti-inflammatory principles.  Planta Medica. 2001;  67 312-6
• 78 Su B -N, Takaishi Y, Kusumi T. Morinols A-L, twelve novel sesquineolignans and neolignans with a new carbon skeleton from Morina chinensis .  Tetrahedron. 1999;  55 14 571-86
• 79 Chavali S R, Forse R A. Decreased production of interleukin-6 and prostaglandin E₂ associated with inhibition of delta-5 desaturation of omega6 fatty acids in mice fed safflower oil diets supplemented with sesamol.  Prostaglandins, Leukotrienes and Essential Fatty Acids. 1999;  61 347-52
• 80 Utsunomiya T, Chavali S R, Zhong W W, Forse R A. Effects of sesamin-supplemented dietary fat emulsions on the ex vivo production of lipopolysaccharide-induced prostanoids and tumor necrosis factor α in rats.  The American Journal of Clinical Nutrition. 2000;  72 804-8
• 81 Ahn K S, Jung K Y, Kim J H, Oh S R, Lee H K. Inhibitory activity of lignan components from the flower buds of Magnoliae fargesii on the expression of cell adhesion molecules.  Biological & Pharmaceutical Bulletin. 2001;  24 1085-7
• 82 Sylvester J, Liacini A, Li W Q, Dehnade F, Zafarullah M. Tripterygium wilfordii Hook F extract suppresses proinflammatory cytokine-induced expression of matrix metalloproteinase genes in articular chondrocytes by inhibiting activating protein-1 and nuclear factor-κB activities.  Molecular Pharmacology. 2001;  59 1196-205
• 83 Allison A C, Cacabelos R, Lombardi V RM, Álvarez X A, Vigo C. Celastrol, a potent antioxidant and anti-inflammatory drug, as a possible treatment for Alzheimer’s disease.  Progress Neuro-Psychopharmacology & Biological Psychiatry. 2001;  25 1341-57
• 84 Koch E, Klaas C A, Rungeler P, Castro V, Mora G, Vichnewski W, Merfort I. Inhibition of inflammatory cytokine production and lymphocyte proliferation by structurally different sesquiterpene lactones correlates with their effect on activation of NF-kappaB.  Biochemical Pharmacology. 2001;  62 795-801
• 85 Schnyder B, Schnyder-Candrian S, Panski A, Bömmel H, Heim M, Duschl A, Moser R. Phytochemical inhibition of interleukin-4-activated Stat6 and expression of VCAM-1.  Biochemical and Biophysical Research Communications. 2002;  292 841-7
• 86 Humar M, Garcia-Pineres A J, Castro V, Merfort I. Effect of sesquiterpene lactones on the expression of the activation marker CD69 and of IL-2 in T-lymphocytes in whole blood.  Biochemical Pharmacology. 2003;  65 1551-63
• 87 Cho J Y, Yoo E S, Baik K U, Park M H, Han B H. In vitro inhibitory effect of protopanaxadiol ginsenosides on tumor necrosis factor (TNF)-alpha production and its modulation by known TNF-alpha antagonists.  Planta Medica. 2001;  67 13-8
• 88 Kim Y K, Kim R G, Park S J, Ha J H, Choi J W, Park H J, Lee K T. In vitro anti-inflammatory activity of kalopanaxsaponin A isolated from Kalopanax pictus in murine macrophage RAW 264.7 cells.  Biological & Pharmaceutical Bulletin. 2002;  25 72-6
• 89 Huang F C, Chan W K, Moriarty K J, Zhang D C, Chang M, He W, Yu K T, Zilberstein A. Novel cytokine release inhibitors. Part I: triterpenes.  Bioorganic & Medical Chemistry Letters. 1998;  8 1883-6
• 90 Duan H, Takaishi Y, Momota H, Ohmoto Y, Taki T, Jia Y, Li D. Immunosuppressive sesquiterpene alkaloids from Tripterygium wilfordii .  Journal of Natural Products. 2001;  64 582-7
• 91 Cho J Y, Park J, Yoo E S, Baik K U, Jung J H, Lee J, Park M H. Inhibitory effect of sesquiterpene lactones from Saussurea lappa on tumor necrosis factor-alpha production in murine macrophage-like cells.  Planta Medica. 1998;  64 594-7
• 92 Jung J H, Ha J Y, Min K R, Shibata F, Nakagawa H, Kang S S, Chang I M, Kim Y. Reynosin from Sassurea lappa as inhibitor on CINC-1 induction in LPS-stimulated NRK-52E cells.  Planta Medica. 1998;  64 454-5
• 93 Hunter M S, Corley D G, Carron C P, Rowold E, Kilpatrick B F, Durley R C. Four new clerodane diterpenes from the leaves of Casearia guianensis which inhibit the interaction of leukocyte function antigen 1 with intercellular adhesion molecule 1.  Journal of Natural Products. 1997;  60 894-9
• 94 Hart P H, Brand C, Carson C F, Riley T V, Prager R H, Finlay-Jones J J. Terpinen-4-ol, the main component of the essential oil of Malaleuca alternifolia (tea tree oil), suppresses inflammatory mediator production by activated human monocytes.  Inflammation Research. 2000;  49 619-26
• 95 Jeong H J, Koo H N, Na H J, Kim M S, Hong S H, Eom J W, Kim K S, Shin T Y, Kim H M. Inhibition of TNF-alpha and IL-6 production by Aucubin through blockade of NF-kappaB activation RBL-2H3 mast cells.  Cytokine. 2002;  18 252-9
• 96 An S J, Pae H O, Oh G S, Choi B M, Jeong S, Jang S I, Oh H, Kwon T O, Song C E, Chung H T. Inhibition of TNF-alpha, IL-1beta, and IL-6 productions and NF-kappa B activation in lipopolysaccharide-activated RAW 264.7 macrophages by catalposide, an iridoid glycoside isolated from Catalpa ovata G. Don (Bignoniaceae).  International Immunopharmacology. 2002;  2 1173-81
• 97 Killestein J, Hoogervorst E L, Reif M, Blauw B, Smits M, Uitdehaag B M, Nagelkerken L, Polman C H. Immunomodulatory effects of orally administered cannabinoids in multiple sclerosis.  Journal of Neuroimmunology. 2003;  137 140-3
• 98 Soares M B, Bellintani M C, Ribeiro I M, Tomassini T C, Ribeiro dos Santos R. Inhibition of macrophage activation and lipopolysaccaride-induced death by seco-steroids purified from Physalis angulata L.  European Journal of Pharmacology. 2003;  459 107-12
• 99 Tanaka S, Tajima M, Tsukada M, Tabata M. A comparative study on anti-inflammatory activities of the enantiomers, shikonin and alkannin.  Journal of Natural Products. 1986;  49 66-9
• 100 Chen X, Oppenheim J, Howard O MZ. Shikonin, a component of anti-inflammatory Chinese herbal medicine, selectively blocks chemokines binding to CC chemokines receptor-1.  International Immunopharmacology. 2001;  1 229-36
• 101 Shen Y -C, Chou C -J, Chiou W -F, Chen C -F. Anti-inflammatory effects of the partially purified extract of radix Stephanie tetrandrae: comparative studies of its active principles tetrandrine and fangchinoline on human polymorphonuclear leukocyte functions.  Molecular Pharmacology. 2001;  60 1983-90
• 102 Choi H S, Kim H S, Min K R, Kim Y, Lim H K, Chang Y K, Chung M W. Anti-inflammatory effects of fangchinoline and tetrandrine.  Journal of Ethnopharmacology. 2000;  69 173-9
• 103 Onai N, Tsunokawa Y, Suda M, Watanabe N, Nakamura K, Sugimoto Y, Kobayashi Y. Inhibitory effects of bisbenzylisoquinoline alkaloids on induction of proinflammatory cytokines, interleukin-1 and tumor necrosis factor-alpha.  Planta Medica. 1995;  61 497-501
• 104 Asahina A, Tada Y, Nakamura K, Tamaki K. Colchicine and griseofulvin inhibit VCAM-1 expression on human vascular endothelial cells - evidence for the association of VCAM-1 expression with microtubules.  Journal of Dermatological Science. 2001;  25 1-9
• 105 Kiraz S, Ertenli I, Arici M, Calguneri M, Haznedaroglu I, Celik I, Pay S, Kirazli S. Effects of colchicine on inflammatory cytokines and selectins in familial Mediterranean fever.  Clinical and Experimental Rheumatology. 1998;  16 721-4
• 106 Perico N, Ostermann D, Bontempeill M, Morigi M, Amuchastegui C S, Zoja C, Akalin E, Sayegh M H, Remuzzi G. Colchicine interferes with L-selectin and leukocyte function-associated antigen-1 expression on human T lymphocytes and inhibits T cell activation.  Journal of the American Society of Nephrology. 1996;  7 594-601
• 107 Chiou W F, Peng C H, Chen C F, Chou C J. Anti-inflammatory properties of piperlactam S: modulation of complement 5a-induced chemotaxis and inflammatory cytokines production in macrophages.  Planta Medica. 2003;  69 9-14
• 108 Yesilada E, Üstün O, Sezik E, Takaishi Y, Ono Y, Honda G. Inhibitory effects of Turkish folk remedies on inflammatory cytokines: interleukin-1α, interleukin-1β and tumor necrosis factor α.  Journal of Ethnopharmacology. 1997;  58 59-73