Immunomodulatory leads from medicinal plants
Pulok K Mukherjee1,*, Neelesh K Nema1, Santanu Bhadra1, D Mukherjee1, Fernão C Braga2 & Motlalepula G Matsabisa3
1School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata - 700 032, India; 2 Faculty of Pharmacy, Universidade Federal de Minas Gerais, Av. Olegário Maciel, 2360, Belo Horizonte, Brazil; 3 South African Medical
Research Council, Francie van Zijl Drive, Parow Valley, Cape Town, South Africa E-mail: naturalproductm@gmail.com
Received 19.03.13, revised 23.08.13
Immunomodulation is the alteration of immune response which may increase or decrease the immune responsiveness.
Medicinal plants, since times immemorial, have been used virtually in all cultures as a source of medicine for altering the immune systems. Several medicinal plants have been investigated for immunomodulatory potentials and they are proved to have beneficial effect on alteration of immune system by diverse mechanisms in animals. The present review will provide an up to date knowledge about the medicinal plants used as immunomodulators and their phytoconstituents. This article highlights on the phytochemistry, pharmacology, therapeutic usage and related aspects of 55 medicinal plants, such as Allium sativum, Aloe vera, Andrographis paniculata, Azadirachta indica, Boerhaavia diffusa, Boswellia serrata, Curcuma longa, Centella asiatica, Carica papaya, Datura quercifolia, Emblica officinalis, Hydrastis Canadensis, Hypericum perforatum, Ocimum sanctum, Panax ginseng, Plantago major, Plantago asiatica, Piper longum, Tinospora cordifolia, Mangifera indica, Momordica charantia, Withania somnifera, etc. which have been investigated for their immunomodulatory potentials, and they are proved to acquire beneficial effect on alteration of immune system by diverse mechanisms. Thus an approach for integration of the available information on several species of medicinal plants used as immunomodulators along with the metabolites responsible for the same has been made in this article.
Keywords: Immunomodulation, Medicinal plants, Natural immunomodulators IPC Int. Cl.8: A61K 36/00, A01C 1/08, A61K 39/00
The term "immunomodulation" means the alteration of immune response which may increase or decrease the immune responsiveness. Enhancement in the immune responsiveness is called immunostimulation and reduction in the immune responsiveness is called immunosuppression. An immunomodulators may be defined as a substance, biological of synthetic, which can stimulate, suppress or modulate any of the components of the immune system including both innate and adaptive arms of the immune response.
The essence of immunomodulation is that a pharmacological agent acting under various dose and time regimens displays an immunomodulating effect1,2. Possible mechanism of immunomodulation has been summarized in Fig. 1.
The extreme manifestations of immunomodulating action of biologically active substances are immunosuppression and immunostimulation, hence both immunostimulating agents and immunosuppressing agents have their own standing and search for better agents exerting these activities is
becoming the field of major interest all over the world3. Natural adjuvants, synthetic agents, antibody reagents are used as immunosuppressive and immunostimulative agents. But there are major limitation to the general use of these agents such as increased risk of infection and generalized effect throughout the immune system4. To overcome these problems a number of drugs from natural source either herbal or mineral have been used as to alter the human immune system5. There are several medicinal plants are employed in different system of medicine throughout the world to improve the immunological disorders. In India use of plants as remedy can be traced back to 6000 BC. Ayurveda – ancient science of life is believed to be prevalent for last 5000 yrs in India6, 7. In recent times modulation of immune response to cure various diseases has been a very interesting concept and the concept of rasayana in ayurveda deals with the same. Ayurvedic system of medicine describes this concept of rasayana under which plants with rejuvenating activity have been described by the emphasis on promotion of health by strengthening host defenses against different diseases.
They have been categorized by ayurveda as ‘Rasayan’
______________
*Corresponding author
literally meaning a house or place of ‘Ras’, i.e.
essential vehicle of life. These plants have been found to have role in the promotion of health by strengthening host defences against different diseases.
Beside that these rasayana plants also have other properties like delaying the onset of senescence and improving mental functions by strengthening the psycho-neuro-immune axis8. Therefore a number of plants with their extracts, active fractions have been investigated for immune response modifying activity (Table 1). In addition, biologically active compounds from natural sources have always been of great interest to scientists working on infectious diseases9 or to improve immune function. Hence, in this review attempt has been made to highlight the experimental work on immunomodulation of various Indian medicinal plants along with their possible mechanism of action with possible constituenrts.
Medicinal plants and their constituents with immunomodulatory potentials
Structures of some important phytoconstituents have given separately in the text from serial No. 1-32
Acorus calamus L. (Araceae)
Acorus calamus commonly known as “Bach or Vacha or Sweet Flag” is a semi-aquatic herb with creeping rhizomes and sword shaped long leaves found throughout India near marshy places, river banks and lakes. The plant showed diverse pharmacological potentials including antibacterial, sedative, spasmolytic, hypocholesterolaemic, insecticide, antiulcer, etc.10. Ethanolic extract of rhizome of the plant proved to possesses anti-cellular and immunomodulatory properties. This extract inhibited proliferation of mitogen and antigen stimulated human peripheral blood mononuclear cells (PBMCs). Further rhizome extract also inhibited growth of several cell lines of mouse and human origin, production of nitric oxide, interleukin-2 (IL-2) and tumor necrosis factor-a (TNF-α)11.
Aloe vera (L.) Burm.f. (Asphodelaceae)
Aloe vera is a very well known medicinal plant, grows in arid climates and widely distributed in Africa and other arid areas. It is claimed that Aloe vera has wound and burn healing properties and also posses a strong anti-inflammatory and immunomodulatory effects. The effects of Aloe vera on microcirculation and levels of TNF-α and IL-6 were investigated in rats after inducing burn. It was found that the amount of leukocyte adhesion was significantly reduced in the Aloe vera treated burn-
wound rats compared to rats in the control group. It was also observed that the levels of TNF-α and IL-6 reduce significantly12. Dihydrocoumarin derivatives (1, 2) were isolated from Aloe vera which exhibited immunomodulatory activity in relation to increasing the phagocytic activity and stimulating the production of superoxide anions in the oxygen respiratory burst of rat peritoneal macrophages13.
Allium sativum L. (Alliaceae)
Allium sativum (Garlic) is an essential dietary component cultivated throughout India, and familiar worldwide as garlic. There is some evidence for immunomodulatory effect of garlic or selected garlic constituents showing increased T-lymphocyte blastogenesis and phagocytosis, as well as modulation of cytokine production in vitro and in vivo. Kyo et al. (2001) have found that aged garlic extract showed variety of anti allergic and antitumor through tumor cell growth inhibition and chemopreventative effects14. They demonstated that histamine release in the rat basophil cell line RBL-2H3 was induced by mouse anti-trinitrophenyl (TNP) monoclonal antibody and the TNP-bovine serum albumin (BSA) hapten carrier complex. The extract at doses of 1.25, 2.5 and 5.0 gm/100 gm significantly inhibited the antigen specific histamine release by 50, 80 and 90%, respectively. Oral administration of extract (10 ml/kg) also decreased 25–45% of the ear swelling, used as an index of immunoglobulin IgE mediated skin reaction. In the psychological stress model, the extract significantly prevented the decrease in spleen weight andrestored the reduction of anti-SRBC hemolytic plaque-forming cells caused by the electrical stress20. It is also reported that at low concentration garlic extract
Fig. 1Mechanism of immunomodulation
Table 1Medicinal plants possessing immunomodulatory properties(Cond.)
Sl No. Plant name Parts used Immunomodulatory mechanism References
1. Eclipta prostrata (L.) L.
(Asteraceae)
Whole plant Induces phagocytic index, antibody titer of mice Increase non-specific immune response and lysosomal activity of the humoral responses
41
2. Phyllanthus emblica L.
(Euphorbiaceae)
Fruits Imunosuppressive effects on lymphocyte proliferation Restoration of IL-2 and IFN- γ production
43
3. Evolvulus alsinoides (L.) L.
(Convolvulaceae)
Whole plant Decreases the level of nitric oxide synthase (NOS) Exert adaptogenic properties
44 4. Ficus benghalensis L.
(Moraceae)
Whole plant Enhance the phagocytosis of the human neutrophils in vitro
Increase the antibody titer value
45
5. Glycyrrhiza glabra L.
(Leguminosae)
Bark & root Enhanced immune and antioxidant enzyme activities Stimulates immune cells by CD69 expression on CD4 and CD8 T cells and macrophages function
46, 47
6. Hippophae rhamnoides L . (Elaeagnaceae)
Leaves & fruits Inhibits chromium-induced free radical production, apoptosis, DNA fragmentation
Stimulates IL-2 and IFN-γ production
48
7. Hydrastis canadensis L.
(Ranunculaceae)
Root Reduces plasma TNF-α, IFN- γ and NO levels Inhibits the T helper -type 2 cytokine profile
49 8. Hypericum perforatum L.
(Hypericaceae)
Aerial parts Increase candidacidal activity of neutrophils and decreased adhesion function of epithelial cells Alter the function of NF-kB
50
9. Jatropha curcas L.
(Euphorbiaceae)
Leaves Increase the antibody titers, lymphocyte and macrophage cells
51 10. Mangifera indica L.
(Anacardiaceae)
Fruits Increase in humoral antibody (HA) titre and DTH Enhance production of IgG1 and IgG2b
52 11. Matricaria chamomilla L.
(Asteraceae)
Flowers Activation of immune cells of peripheral blood, and increased sensitivity of effector cells to helper signals
53 12. Mollugo verticillata L.
(Molluginaceae)
Leaves Inhibits the production of NO 54
13. Momordica charantia L.
(Cucurbitaceae)
Fruits & seeds Inhibits the release of TNF-α, NO and proliferation of spleen cells induced by PHA and Con A
55 14. Morinda citrifolia L.
(Rubiaceae)
Fruits Stimulating the release TNF-α, IL-β, IL-10, IL-12, IFN-γ
56 15. Nelumbo nucifera
Gaertn.(Nymphaeceae)
Rhizome & seed Reduce NO production, protects mast cells degranulation
Express CD40, CD80, CD86
59,60
16. Nerium oleander L.
(Apocynaceae)
Leaves Inhibited haemaglutination antibodies, DTH reaction, phagocytic index etc in mice
61 17. Nigella sativa L.
(Ranunculaceae)
Seeds Reduces pancreatic ductal adenocarcinoma cell (PDA) synthesis of monocyte chemoattractant protein-1 (MCP-1), TNF- α , IL-1β and cyclooxigenase (COX) -2 Inhibits the polymorpho nuclear leukocytes functions
62
18. Ocimum tenuiflorum L.
(Labiatae)
Aerial parts Inhibits antigen induced histamine release from the peritoneal mast cells, foot pad thickness and leucocyte migration
63
19. Plantago species (Plantago major L.
& P. asiatica L. (Plantaginaceae)
Seed It expressed higher levels of MHC class II molecules and costimulatory molecules such as CD80 and CD86 It acts on human peripheral blood mononuclear cells (PBMC) through lymphocyte transformation; enhance the secretion of IFN-γ.
64
20. Piper longum L.
(Piperaceae)
Fruits & leaves Increase the total WBC count, bone marrow
cellularity, α- esterase positive cells, enhance the total antibody production
65
(Table 1-Contd.)
Table 1Medicinal plants possessing immunomodulatory properties
Sl No. Plant name Parts used Immunomodulatory mechanism References
21. Acorus calamus L. (Araceae) Rhizome Increase the production of IL-2, tumor necrosis factor (TNF)-α
11 22. Aloe vera (L.) Burm.f.
(Asphodelaceae)
Leaves Increases phagocytosis and stimulating the production of superoxide
12, 13 23. Allium sativum L. (Alliaceae) Fruits Suppress leukocyte inflammatory cytokine production 14,15 24. Andrographis paniculata Wall. ex
Nees (Acanthaceae)
Aerial parts Increase the production of IL-2, Inhibits of NO production
17 25. Azadirachta indica A. Juss.
(Meliaceae)
Leaves Increase IgM and IgG production
Inhibits of NO synthesis, degranulation of neutrophils
18 26. Asparagus racemosus Willd
(Liliaceae)
Root Increase the production of leucocytosis
Enhances the phagocytic activity of the macrophages
20 27. Argyreia speciosa (L. f.) Sweet
(Convolvulaceae)
Root & seeds Enhance the production of circulating antibody titre Increase in DTH reaction
21 28. Baliospermum montanum (Willd.)
Müll.Arg. (Euphorbiaceae)
Root & leaves Enhances neutrophil phagocytic function such as neutrophil locomotion, chemotaxis
Stabilized mast cell degranulation induced by compound 48/80.
22
29. Bidens pilosa L. (Asteraceae) Whole plant Enhances the cytokine production and white blood cells population
Increases IFN-γ promoter activity
23
30. Boerhaavia diffusa L.
(Nyctaginaceae)
Root Inhibits human NK cell cytotoxicity in vitro Inhibits production of NO, IL-2 and TNF-α
24 31. Boswellia serrata Roxb. ex Colebr.
(Burseraceae)
Bark Inhibits passive paw anaphylaxis reaction and mast cells protection
26 32. Calendula officinalis L.
(Asteraceae)
Leaves & flowers Inhibits tumor cell proliferation 28 33. Camellia sinensis (L.) Kuntze
(Theaaceae)
Leaves Enhances the neopterin production in peripheral mononuclear cells
29 34. Capparis zeylanica L
(Capparidaceae)
Leaves Prevents myelosupression in mice with cyclophosphamide and potentiats DTH reaction
30 35. Carica papaya L.
(Caricaceae)
Leaves & seeds It enhances the phytohemagglutinin responsiveness of lymphocytes
It inhibits the classical complement-mediated hemolytic pathway
31
36. Centella asiatica (L.) Urban. (Umbelliferae)
Leaves It increases the phagocytic index, total WBC count and Inhibited human peripheral blood mononuclear cell (PBMC) mitogenesis and production of IL-2 and TNF-α
32
37. Chelidonium majus L.
(Papaveraceae)
Aerial parts Exert antitumor immunostimulatory effect 33 38. Chrysanthemum indicum L.
(Compositae)
Aerial parts Increases DTH reaction, antibody generation, Potentiates the mononuclear phagocytosis function
34 39. Cichorium intybus L.
(Asteraceae)
Root Increases DTH reaction, phagocytic activity and natural killer (NK) cell activity and IFN-γ secretion
35 40. Citrus aurantiifolia (Christm.)
Swingle (Rutaceae)
Fruits & leaves Inhibits proliferation of PHA activated mononuclear cells, staphylococcal protein
36 41. Cryptolepis dubia (Burm.f.)
M.R.Almeida. (Apocynaceae)
Root It stimulates the DTH reaction and also increases the humoral antibody production
37 42. Curcuma longa L.
(Zingiberaceae)
Rhizome It shows immunomodulation through inhibition of proliferation induced by PMA and anti-CD28 antibody. Also it inhibits the T lymphocytes isolated from healthy donors induced by PHA
38,39
43. Desmodium gangeticum (L.) DC.
(Fabaceae)
Whole plant Enhance NO production and provided resistance against infection established in peritoneal macrophages by the protozoan parasite Leishmania donovani
40
(Table 1-Contd.)
Table 1Medicinal plants possessing immunomodulatory properties
Sl No. Plant name Parts used Immunomodulatory mechanism References
44. Acorus calamus L. (Araceae) Rhizome Increase the production of IL-2, tumor necrosis factor (TNF)-α
11 45. Aloe vera (L.) Burm.f.
(Asphodelaceae)
Leaves Increases phagocytosis and stimulating the production of superoxide
12, 13 46. Allium sativum L. (Alliaceae) Fruits Suppress leukocyte inflammatory cytokine production 14,15 47. Andrographis paniculata Wall. ex
Nees (Acanthaceae)
Aerial parts Increase the production of IL-2, Inhibits of NO production
17 48. Azadirachta indica A. Juss.
(Meliaceae)
Leaves Increase IgM and IgG production
Inhibits of NO synthesis, degranulation of neutrophils
18 49. Asparagus racemosus Willd
(Liliaceae)
Root Increase the production of leucocytosis
Enhances the phagocytic activity of the macrophages
20 50. Argyreia speciosa (L. f.) Sweet
(Convolvulaceae)
Root & seeds Enhance the production of circulating antibody titre Increase in DTH reaction
21 51. Baliospermum montanum (Willd.)
Müll.Arg. (Euphorbiaceae)
Root & leaves Enhances neutrophil phagocytic function such as neutrophil locomotion, chemotaxis
Stabilized mast cell degranulation induced by compound 48/80.
22
52. Bidens pilosa L. (Asteraceae) Whole plant Enhances the cytokine production and white blood cells population
Increases IFN-γ promoter activity
23
53. Boerhaavia diffusa L.
(Nyctaginaceae)
Root Inhibits human NK cell cytotoxicity in vitro Inhibits production of NO, IL-2 and TNF-α
24 54. Boswellia serrata Roxb. ex Colebr.
(Burseraceae)
Bark Inhibits passive paw anaphylaxis reaction and mast cells protection
26 55. Calendula officinalis L.
(Asteraceae)
Leaves & flowers Inhibits tumor cell proliferation 28 56. Camellia sinensis (L.) Kuntze
(Theaaceae)
Leaves Enhances the neopterin production in peripheral mononuclear cells
29 57. Capparis zeylanica L
(Capparidaceae)
Leaves Prevents myelosupression in mice with cyclophosphamide and potentiats DTH reaction
30 58. Carica papaya L.
(Caricaceae)
Leaves & seeds It enhances the phytohemagglutinin responsiveness of lymphocytes
It inhibits the classical complement-mediated hemolytic pathway
31
59. Centella asiatica (L.) Urban. (Umbelliferae)
Leaves It increases the phagocytic index, total WBC count and Inhibited human peripheral blood mononuclear cell (PBMC) mitogenesis and production of IL-2 and TNF-α
32
60. Chelidonium majus L.
(Papaveraceae)
Aerial parts Exert antitumor immunostimulatory effect 33 61. Chrysanthemum indicum L.
(Compositae)
Aerial parts Increases DTH reaction, antibody generation, Potentiates the mononuclear phagocytosis function
34 62. Cichorium intybus L.
(Asteraceae)
Root Increases DTH reaction, phagocytic activity and natural killer (NK) cell activity and IFN-γ secretion
35 63. Citrus aurantiifolia (Christm.)
Swingle (Rutaceae)
Fruits & leaves Inhibits proliferation of PHA activated mononuclear cells, staphylococcal protein
36 64. Cryptolepis dubia (Burm.f.)
M.R.Almeida. (Apocynaceae)
Root It stimulates the DTH reaction and also increases the humoral antibody production
37 65. Curcuma longa L.
(Zingiberaceae)
Rhizome It shows immunomodulation through inhibition of proliferation induced by PMA and anti-CD28 antibody. Also it inhibits the T lymphocytes isolated from healthy donors induced by PHA
38,39
66. Desmodium gangeticum (L.) DC.
(Fabaceae)
Whole plant Enhance NO production and provided resistance against infection established in peritoneal macrophages by the protozoan parasite Leishmania donovani
40
(Table 1-Contd.)
Table 1Medicinal plants possessing immunomodulatory properties(Cond.)
Sl No. Plant name Parts used Immunomodulatory mechanism References
67. Eclipta prostrata (L.) L.
(Asteraceae)
Whole plant Induces phagocytic index, antibody titer of mice Increase non-specific immune response and lysosomal activity of the humoral responses
41
68. Phyllanthus emblica L.
(Euphorbiaceae)
Fruits Imunosuppressive effects on lymphocyte proliferation Restoration of IL-2 and IFN- γ production
43 69. Evolvulus alsinoides (L.) L.
(Convolvulaceae)
Whole plant Decreases the level of nitric oxide synthase (NOS) Exert adaptogenic properties
44 70. Ficus benghalensis L.
(Moraceae)
Whole plant Enhance the phagocytosis of the human neutrophils in vitro
Increase the antibody titer value
45
71. Glycyrrhiza glabra L.
(Leguminosae)
Bark & root Enhanced immune and antioxidant enzyme activities Stimulates immune cells by CD69 expression on CD4 and CD8 T cells and macrophages function
46, 47
72. Hippophae rhamnoides L . (Elaeagnaceae)
Leaves & fruits Inhibits chromium-induced free radical production, apoptosis, DNA fragmentation
Stimulates IL-2 and IFN-γ production
48
73. Hydrastis canadensis L.
(Ranunculaceae)
Root Reduces plasma TNF-α, IFN- γ and NO levels Inhibits the T helper -type 2 cytokine profile
49 74. Hypericum perforatum L.
(Hypericaceae)
Aerial parts Increase candidacidal activity of neutrophils and decreased adhesion function of epithelial cells Alter the function of NF-kB
50
75. Jatropha curcas L.
(Euphorbiaceae)
Leaves Increase the antibody titers, lymphocyte and macrophage cells
51 76. Mangifera indica L.
(Anacardiaceae)
Fruits Increase in humoral antibody (HA) titre and DTH Enhance production of IgG1 and IgG2b
52 77. Matricaria chamomilla L.
(Asteraceae)
Flowers Activation of immune cells of peripheral blood, and increased sensitivity of effector cells to helper signals
53 78. Mollugo verticillata L.
(Molluginaceae)
Leaves Inhibits the production of NO 54
79. Momordica charantia L.
(Cucurbitaceae)
Fruits & seeds Inhibits the release of TNF-α, NO and proliferation of spleen cells induced by PHA and Con A
55 80. Morinda citrifolia L.
(Rubiaceae)
Fruits Stimulating the release TNF-α, IL-β, IL-10, IL-12, IFN-γ
56 81. Nelumbo nucifera
Gaertn.(Nymphaeceae)
Rhizome & seed Reduce NO production, protects mast cells degranulation
Express CD40, CD80, CD86
59,60
82. Nerium oleander L.
(Apocynaceae)
Leaves Inhibited haemaglutination antibodies, DTH reaction, phagocytic index etc in mice
61 83. Nigella sativa L.
(Ranunculaceae)
Seeds Reduces pancreatic ductal adenocarcinoma cell (PDA) synthesis of monocyte chemoattractant protein-1 (MCP-1), TNF- α , IL-1β and cyclooxigenase (COX) -2 Inhibits the polymorpho nuclear leukocytes functions
62
84. Ocimum tenuiflorum L.
(Labiatae)
Aerial parts Inhibits antigen induced histamine release from the peritoneal mast cells, foot pad thickness and leucocyte migration
63
85. Plantago species (Plantago major L.
& P. asiatica L. (Plantaginaceae)
Seed It expressed higher levels of MHC class II molecules and costimulatory molecules such as CD80 and CD86 It acts on human peripheral blood mononuclear cells (PBMC) through lymphocyte transformation; enhance the secretion of IFN-γ.
64
86. Piper longum L.
(Piperaceae)
Fruits & leaves Increase the total WBC count, bone marrow
cellularity, α- esterase positive cells, enhance the total antibody production
65
(Table 1-Contd.)
significantly reduced that IL-12 production, but IL-10 production was increased. The TNF-α (tumor necrosis factor), IL-1α, IL-6, IL-8, Tcell interferon-gamma (IFN-γ), IL-2, and TNF-α were observed to decreased significantly with the extract15.
Andrographis paniculata (Burm.f.) Wall. ex. Nees. (Acanthaceae)
Andrographis paniculata is one of the Chinese and Indian herbs reputed to be effective in the treatment of cold, diarrhea, fever, and inflammation, etc.16. Methanolic extract of A. paniculata has potential for anticancer and immunomodulatory activities in human cancer and immune cells. The extract and its dichloromethane fraction significantly inhibited the proliferation of HT-29 (colon cancer) cells and augment the proliferation human peripheral blood lymphocytes low concentrations. Three diterpene compounds were isolated from the plant, viz.
andrographolide (3), 14-deoxyandrographolide and 14-deoxy-11, 12-didehydroandrographolide.These molecules showed enhanced proliferation and
interleukin-2 (IL-2) induction in human peripheral blood lymphocytes23. It was also reported that andrographolide exhibits nitric oxide (NO) inhibitory property in endotoxin-stimulated macrophages17.
Azadirachta indica A. Juss. (Meliaceae)
Azadirachta indica is well known in India and its neighbouring countries for more than 2000 yrs as one of the most versatile medicinal plants having a wide spectrum of biological activity including anti- inflammatory, anti-diabetic, antiviral, anticarcinogenic, immunostimultory, etc. Aqueous extract of stem bark has been shown to enhance the immune response of Balb-c mice to sheep red blood cells in-vivo. The aqueous extract showed strong anticomplementary effects with dose, time-dependently, and most pronounced in the classical complement pathway assay. In addition, a dose-dependent decrease in the chemiluminescence of polymorphonuclear leukocytes and a dose-dependent increase in the production of migration inhibition factor by lymphocytes were also
Table 1Medicinal plants possessing immunomodulatory properties(Cond.)
Sl No. Plant name Parts used Immunomodulatory mechanism References
87. Premna tomentosa Willd.
(Verbanaceae)
Stem bark Decrease the lymphocyte proliferation and antioxidant levels
66 88. Prunella vulgaris L.
(Lamiaceae)
Fruits Stimulates the proliferation of T-lymphocytes and suppressed NO production in lipopolysaccharide- stimulated macrophages
67
89. Psoralea corylifolia L.
(Fabaceae)
Leaves Up regulates the production of OVA-specific Th1 cytokine (IFN-γ) and down regulated OVA-specific Th2 cytokine
68
90. Punica granatum L.
(Punicaceae)
Fruits Inhibits the leucocyte migration 69
91. Rhinacanthus nasutus (L.) Kurz.
(Acanthaceae)
Whole plant Increased the production of IL-2 and TNF-α 33 92. Salvia officinalis L.
(Lamiaceae)
Aerial parts Induce rat thymocyte proliferation 70
93. Tamarindus indica L. (Leguminosae) Fruits Inhibits the phorbol myristate acetate (PMA) stimulated neutrophil function, neutrophil NADPH oxidase activity, and elastase activity
71,72
94. Terminalia chebula Retz.
(Combretaceae)
Fruits Increase in HA titer and DTH reaction 73
95. Tinospora cordifolia (Willd.) Miers (Menispermaceae)
Stem & root Increase the total white blood cell count, bone marrow cellularity and α-esterase positive cells
Enhance the macrophage activation
74
96. Trigonella foenum-graecum L.
(Fabaceae)
Seeds Increases the phagocytic index and phagocytic capacity of macrophages, enhancement of thymus and bone marrow cellularities
75
97. Urtica dioica L.
(Urticaceae)
Aerial parts Reduce TNF-α and other inflammatory cytokines by inhibiting the genetic transcription factor
76 98. Withania somnifera (L.) Dunal
(cultivated var.) (Solanaceae)
Root Increase total WBC count, bone marrow cellularity, circulating antibody titer, plaque forming cells in the spleen, phagocytic activity of macrophages
77
observed. Neem oil has been shown to possess immunostimulant activity by selectively activating the cell-mediated immune mechanisms to elicit an enhanced response to subsequent mitogenic or antigenic challenge. Neem oil also possesses immunomodulatory effects in mice. The intraperitoneal (i.p.) injection of neem oil in mice showed increased in leukocytic cells after 3 days of treatment. In addition, the peritoneal macrophages of mice exhibited enhanced phagocytic activity and expression of MHC class-II antigens. Nimbidin is a mixture of tetranortriterpenes and is the major active principle of the seed oil of A.
indica possessing potent antiinflammatory and antiarthritic activities by inhibiting some of the functions of macrophages and neutrophils relevant to the inflammatory response following both in vivo and in-itro exposure. Oral administration of 5-25 mg/kg nimbidin to rats for 3 consecutive days significantly inhibited the relocation of macrophages to their peritoneal cavities in response to inflammatory stimuli and also inhibited phagocytosis and phorbol-12- myristate-13-acetate (PMA) stimulated respiratory burst in these cells. Nimbidin also inhibited nitric oxide (NO) and prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS) stimulated macrophages following in-vitro exposure. Further observation proved that nimbidin also attenuated degranulation in neutrophils assessed in terms of release of β-glucuronidase, myeloperoxidase and lysozyme18, 19.
Asparagus racemosus Willd (Liliaceae)
Asparagus racemosus (Shatavari) is recommended in Ayurvedic texts for prevention and treatment of gastric ulcers, dyspepsia and as a galactogogue. The Asparagus genus is considered to be of medicinal importance because of the presence of steroidal saponins and sapogenins in various parts of the plant. A. racemosus is commonly mentioned as a rasayana in the Ayurveda.
Immunomodulating property of A. racemosus has been shown to protect the rat and mice against experimental induced abdominal sepsis. Oral administration of decoction of powdered root of A. racemosus has been reported to produce leucocytosis and predominant neutrophilia along with enhanced phagocytic activity of the macrophages and polymorphs. Percentage mortality of A. racemosus treated animals was found to be significantly reduced while survival rate was comparable to that of the group treated with a combination of metronidazole and gentamicin. A. racemosus showed anti-sepsis activity by altering function of macrophages, indicates its possible immunomodulatory property.
Alcoholic extract of A. racemosus has been found to enhance both, humoral and cell mediated immunity of albino mice injected with sheep red blood cells as particulate antigen20.
Argyreia speciosa (L. f.) Sweet (Convolvulaceae)
Argyreia speciosa Sweet of the family convolvulaceae, commonly known as Vryddhadaru in Sanskrit, is a woody climber found throughout in India. It has been used as a ‘rasayana’ drug in the traditional Ayurvedic system of medicine. The roots of this plant have been regarded as alternative and tonic, and are said to be useful in rheumatism and diseases of the nervous system. The ethanolic extract of the root of A. speciosa was showed immunomodulatory activity via DTH reaction, effect on humoral immune responses and phagocytic function of the cells. The extract caused increase in DTH reaction and significantly enhanced the production of circulating antibody titre. This indicates the enhanced responsiveness of macrophages and T and B lymphocytes involved in antibody synthesis21.
Baliospermum montanum (Willd.) Müll.Arg. (Euphorbiaceae)
Baliospermum montanum of family Euphorbiaceae is a stout under shrub with herbaceous branches from the roots. It is found in tropical and subtropical Himalaya from Kashmir eastwards to Arunachal Pradesh. The immunomodulatory activity of B. montanum has not been reported scientifically. The different concentration (25, 50, 100 µg/ml) of aqueous extract of roots of B. montanum has been shown immunomodulatory activity through neutrophil phagocytic function such as neutrophil locomotion, chemotaxis, immunostimulant activity of phagocytosis of killed Candida albicans and qualitative nitroblue tetrazolium test by using human neutrophils22.
Bidens pilosa L. (Asteraceae)
Bidens pilosa is the largest flowering plant family in the world and it is used as an ethnical medicine for bacterial infection or immune modulation in Asia, America and Africa. Aqueous infusion of B. pilosa has an immunolodulatory effect by enhancing the cytokine production and white blood cells population.
Hot water extracts from B. pilosa and its butanol fraction increased IFN-γ promoter activity by 2 to 6 folds. From its butanol fraction the responsible molecules, centaurein (4) (EC50 =75µg/ml) and its aglycone (centaureidin) were isolated which showed
augmentation of IFN-γ promoter activity. Centaurein induced the activity of NFAT and NFκB enhancers, located within the IFN-γ promoter23.
Boerhaavia diffusa L. (Nyctaginaceae)
It is a common plant grows widely in the tropics in both dry and rainy seasons in India, Nigeria and many other countries. Ethanolic extract of B. diffusa root significantly inhibited the human NK cell cytotoxicity in vitro, IL-2 and TNF-α in human PBMCs the cell proliferation production of NO in mouse macrophage cells. It is also observed that intracytoplasmic IFN-γ and cell surface markers such as CD16, CD25, and HLA-DR did not get affected on treatment with B.
diffusa extract24. Solvent fraction of B.diffusa root extract was studied for its effect on cellular and humoral functions in mice. Oral administration of the fraction (25–100 mg/kg) significantly inhibited SRBC-induced delayed hypersensitivity reactions in mice. A significant dose-related increase in antibody titre was observed during pre- and post-immunisation treatment. Eupalitin-3-O-β-D-galactopyranoside (5) isolated from ethanolic extract of B.diffusa which inhibited PHA-stimulated proliferation of peripheral blood mononuclear cells, two-way MLR and NK cell cytotoxicity as well as LPS induced NO production by RAW 264.7. The compound also inhibited production of PHA stimulated IL-2 at the protein and mRNA transcript levels and LPS stimulated TNF-α production in human PBMCs; it also blocked the activation of DNA binding of nuclear factor-KB and AP-1, two major transcription factors centrally involved in expression of the IL-2 and IL-2R gene, which are necessary for T cell activation and proliferation25.
Boswellia serrata Roxb. ex Colebr. (Burseraceae)
Boswellia serrata, or Salai, is one of Ayurveda’s most potent anti-inflammatory herbs. On its own or in combination with other herbs, Boswellia is used both externally and internally to treat rheumatoid arthritis, back pain, fibrositis and osteoarthritis. Clinical trials and animal studies with B. serrata have confirmed its antiinflammatory and pain-relieving effects.
Boswellic acid (6), is a pentacyclic triterpene acid present in the extract of gum resin of B. serrata. It has been reported that boswellic acid effect on cell mediated and humoral immunity. In concentrations greater than 3.9µg/ml of boswellic acids produced almost similar and dose related inhibition of proliferative responsiveness of splenocytes to
mitogens and alloantigen. Preincubation of macrophages with different concentrations of boswellic acid enhanced the phagocytic function of adherent macrophages. Sharma et al. (1998) has reported that boswellic acid has antianaphylactic activity and stabilized the mast cell from degranulation against compound 48/80. A significant inhibition in the compound 48/80 induced degranulation of mast cells in dose-dependant manner (20, 40 and 80 mg/kg, p.o.) was observed26.
Calendula officinalis L. (Asteraceae)
Calendula officinalis is an important plant in Indian medicinal systems which have diverse medicinal uses including anti-viral, anti-genotoxic, anti-inflammatory properties27. Numbers of immunomodulatory effects have also been attributed to this plant. 70% ethanolic extract of C. officinalis showed mitogenic activity on human peripheral blood lymphocytes and thymocytes. The extract also possesses a proliferative responsiveness activity of human lymphocytes and mixed lymphocyte reaction.
The laser activated C. officinalis extract showed a potent in vitro inhibition of tumor cell proliferation on a wide variety of human and murine tumor cell lines.
The inhibition ranged from 70 to 100%. Mechanisms of inhibition were identified as cell cycle arrest in G0/G1 phase and Caspase-3-induced apoptosis28.
Camellia sinensis (L.) Kuntze (Theaaceae)
Camellia sinensis (green tea) is being used as a traditional medicine in Vietnam and China for long time for antitumor, antiviral and immunostimulative properties. The extract of C. sinensis enhanced the neopterin production in unstimulated peripheral mononuclear cells, but an effective reduction of neopterin formation in cells stimulated with concanavalin A, phytohemagglutinin, or interferon-γ was found. It was also reported that the extract of C.
sinensis in combination with low dose cyclosporine A significantly prolongs graft survival as well as increase the production of immunosuppressive cytokine, IL-10. Further the extract decreases cyclosporine A induced high TGF-β production, which is implicated in cyclosporine A induced nephrotoxicity. It was also reported that the extract inhibited both nonspecific and antigen-specific proliferation of T cells in vitro29.
Capparis zeylanica L. (Capparidaceae)
Capparis zeylanica commonly known as Indian caper is a climbing shrub found throughout India and
it has been used as a 'Rasayana' drug in the traditional Ayurvedic system of medicine. The leaves of the plant are extensively used as counter-irritant, febrifuge, treatment in piles, etc. The immunomodulatory activity of ethanolic and water extracts of C. zeylanica leaves have been repoted by Ghule et al. (2006) through several immunomologica parameters including neutrophil adhesion test, humoral response to sheep red blood cells, delayed- type hypersensitivity reaction, phagocytic activity and cyclophosphamide-induced myelosuppression. The water extract of C. zeylanica leaves at 300 mg/kg, oral dose evoke a significant increase in neutrophil adhesion to nylon fibres. The ethanolic extract dose dependenltly increased antibody titres in mice and potentiated the delayed-type hypersensitivity reaction induced by sheep red blood cells. The ethanolic extract also prevented myelosuppression in mice treated with cyclophosphamide drug30.
Carica papaya L. (Caricaceae)
Carica papaya has been traditionally used as ethnomedicine for a number of disorders, including cancer. Various parts including leaves, fruit, seeds, etc. are being used to treat many diseases. Recently C.
papaya seed extract is currently being marketed as a nutritional supplement with purported ability to rejuvenate the body condition and to increase energy.
The product claims to improve immunity against common infection and body functioning. The crude seed extract and two other bioactive fractions significantly enhanced the phytohemagglutinin responsiveness of lymphocytes and significantly inhibited the classical complement-mediated hemolytic pathway. Otsuki et al. (2010) reported that the aqueous extract of C. papaya leaves exhibits anti- tumor activity with significant growth inhibition of tumor cell lines. The production of IL-2 and IL-4 was reduced following the addition of C. papaya leaves extract, whereas that of IL-12p40, IL-12p70, IFN-γ and sTNF-α was enhanced without growth inhibition.
The cytotoxicity of activated Peripheral blood mononuclear cells (PBMC) against K562 was enhanced by the addition of the extract31.
Centella asiatica (L.) Urb. (Umbelliferae)
Centella asiatica is commonly known as
‘mandukparni’. It grows mainly in wet areas in India, upto an altitude of 650 m. The plant has several medicinal uses, i.e. sedative, spasmolytic, anti-anxiety and anti-stress action. It is also reported that C.
asiatica extract and its main constituent asiaticoside (7) possesses immunomodulatory activity, acting by increasing phagocytic index and total WBC count. In human peripheral blood mononuclear cells (PBMCs), Centella asiatica (water extract) significantly increases proliferation and the production of IL-2 and TNF-α In contrast, an ethanol extract of Centella asiatica inhibited human PBMC mitogenesis and the production of IL-2 and TNF-α32.
Chelidonium majus L. (Papaveraceae)
Chelidonium majus has multiple applications in Korean traditional medicine because of its anti- tumoral, cytotoxic, anti-inflammatory and anti- microbial activities and has long been known to have anti-inflammatory effects. C. majus has been investigated for immunomodulatory potential and the results proved that methanolic extract of the plant having pronounced immunomodulatory effects. The methanolic extract significantly suppressed the progression of collagen-induced arthritis and inhibited the production of TNF-α, IL-6 IFN-γ, B cells and γδ T cells in spleen and lymph node. The erosion of cartilage was vividly reduced in mouse knees after treatment of the extract. It was also reported by the author that the same extract increased proportion of CD4+, CD25+ regulatory T cells in vivo. Te levels of IgG and IgM rheumatoid arthritis factor were also decreased with the extract33.
Chrysanthemum indicum L. (Compositae)
Chrysanthemum indicum has long been used in as a traditional medicine in Korea, China, and Japan to treat various immune-related diseases. Recently, it has been reported that 70% ethanolic extract of C.
indicum inhibited skin inflammation in mice by reducing topical edema. Administration of the ethanol extract at 200 mg/kg (i.p.), is leading to substantial reductions in skin thickness and tissue weight, inflammatory cytokine production, neutrophil- mediated myeloperoxidase activity, and various histopathological indicators. In addition, the extract was effective at reducing inflammatory damage induced by chronic 12-O-tetradecanoyl-phorbol-13- acetate (TPA) exposure34.
Cichorium intybus L. (Asteraceae)
Cichorium intybus has an extensive uses in folk medicines in India for the treatment of liver disorders, gallstones, and inflammation of the urinary tract, fever, vomiting, diarrhea, and enlargement of the spleen. It
has been investigated that 70% ethanol extract of the C.
intybus showed a complete inhibitory effect on the proliferation of lymphocytes in the presence of phytohaemaglutinin. Effects of the ethanol extract of C.
intybus on the immunotoxicity of ethanol were also investigated in ICR strain mice. The results revealed that the combination of C. intybus extract and ethanol showed significant increases in the circulating leukocytes and the relative weights of liver, spleen and thymus, as compared with those in mice treated with ethanol alone. In addition, the splenic plaque forming cells and hemagglutination titers to sheep red blood cells, and the secondary IgG antibody response to bovine serum albumin were markedly enhanced by the extract plus ethanol treatment compared to the treatment of ethanol alone. The mice which received the combination of C. intybus extract and ethanol, a significant increase in delayed-type hypersensitivity reaction, phagocytic activity, natural killer cell activity and cell proliferation as well as IFN-γ secretion were also observed35.
Citrus aurantiifolia (Christm.) Swingle (Rutaceae)
In vitro immunomodulatory effect of concentrated juice of Citrus aurantifolia was investigated by Gharagozloo and Ghaderi (2001) using the parameter of production of specific polyclonal antibodies in rabbits. The immunomodulatory effect of the extract was tested in mitogen activated cultured mononuclear cells. The culture results indicated that proliferation of phytohemagglutinin activated mononuclear cells was significantly inhibited by C. aurantifolia juice dose dependently. At the dose of 500 µg/ml of the extract could inhibit proliferation of staphylococcal protein A activated mononuclear cells36.
Cryptolepis dubia (Burm.f.) M.R.Almeida. (Apocynaceae)
The ethanol extract of root of the plant Cryptolepis dubia (Syn: C. buchanani) has been reported to possesses immunomodulatory activity in mice and rats. Oral administration of C. buchanani root extract showed significant stimulation of the delayed type hypersensitivity reaction and humoral antibody production. The oral LD50 was found to be more than 3 gm/kg in both rats and mice37.
Curcuma longa L. (Zingiberaceae)
Curcuma longa, a perennial herb widely distributed in India. The rhizome of C. longa has numerous medicinl uses including analgesic, anti-inflammatory, wound healing and immunomodulatory activities. The chief constituent of C. longa is curcumin (8), which
palyed a major role for immunomodulatory activity.
Bone marrow cellularity, alpha-esterase positive cells and macrophage phagocytic activity were enhanced by Curcumin administration. Numerous evidences suggest that curcumin can modulate both the proliferation and the activation of T cells. It was reported that curcumin inhibits the proliferation induced by PMA and anti- CD28 antibody or that induced by PHA of T lymphocytes isolated from healthy donors38. Yadav et al. (2005) reported that curcumin can suppress the phytohemagglutinin-induced proliferation of human peripheral blood mononuclear cells and inhibit IL-2 expression and NF-κB39.
Desmodium gangeticum (L.) DC. (Fabaceae)
Desmodium gangeticum (L.) is a small shrub of tropical regions that has been used as a bitter tonic, febrifuge, digestive, anticatarrhal and antiemetic in inflammatory conditions of the chest and other organs. D. gangeticum has also been reported to contain alkaloids, flavone and isoflavanoid glycosides. Total alkaloids of this species showed anticholinesterase, smooth muscle stimulant, CNS stimulant and depressant responses. Mishra et al.
(2005) has been reported that aminoglucosyl glycerolipid (9) of D. gangeticum possesses immunomodulatory activities. This compound exhibited in-vitro immunomodulatory activities, as it enhanced nitric oxide (NO) production and provided resistance against infection established in peritoneal macrophages by the protozoan parasite Leishmania donovani40.
Eclipta prostrata (L.) L. (Asteraceae)
The methanol extract of Eclipta prostrata (syn.
Eclipta alba) whole plant that contains 1.6% of wedelolactone showed immunomodulating effect in vivo. Administration of five doses (100 to 500 mg/kg body wt) significantly increased phagocytic index, antibody titer; F ratios of the phagocytic index and WBC count. Heighest linearity patterns of the dose- response relationship were found in case of phagocytic index and lower in the case of antibody titer. In-vivo study showed that the aqueous extract of E. prostrata leaves significantly increased non- specific immune response and lysozyme activity of the humoral responses in Oreochromis mossambicus41
Phyllanthus emblica L. (Euphorbiaceae)
Phyllanthus emblica (syn. Emblica officinalis) or
‘Amla’ is a small or medium size tree found in all
deciduous forests of India. Amla fruits are largely used in Indian medicine. It is used as an acrid, diuretic, refrigerant, laxative, diarrhea and dysentery42. It is a popular ingredient of ‘Triphala’
and ‘Chyawanprash’. The anti-inflammatory response of E. officinalis extract has been well established and predicted mechanism for anti-inflammation is based on its function to reduce lymphocyte proliferation and histopathological severity of synovial hyperplasia43.
Evolvulus alsinoides (L.) L. (Convolvulaceae)
Evolvulus alsinoides is an important and very popular plant in Ayurvedic system of medicine to improve intelligence, memory and higher mental fuctions. The immunomodulatory property of E.
alsinoides extract was investigated and the result exposed that a remarkable reduction in inflammation and edema was observed. The extract also induced that nitric oxide synthase (NOS) significantly. At cellular level immunosuppression occurred during the early phase of the disease. There was mild synovial hyperplasia and infiltration of few mononuclear cells in the extract treated animals44.
Ficus benghalensis L. (Moraceae)
Ficus benghalensis has been used by ayurvedic practitioners, in India to boost the immune system to fight a number of diseases. Gabhe et al. (2006) was investigate for immunomodulatory potential of various extracts of F. Benghalensis. The successive methanol and water extracts exhibited a significant increase in the percentage phagocytic responses and methanol extract was found to exhibit a dose related increase in the hypersensitivity reaction, to the sheep red blood cells antigen, at concentrations of 100 and 200 mg/kg. The methanol extract also significantly increased the antibody titer value dose dependently45.
Glycyrrhiza glabra L. (Leguminosae)
The root extract of Glycyrrhiza glabra is used as a medicine for various diseases including anti- inflammatory as well as anti-allergy46. It was investigated that crude polysaccharide fraction of the shoot and hairy root of G. glabra induced nitric oxide production by murine peritoneal macrophages in- vitro. In addition, the polysaccharide of G. glabra dose-dependently improved immune and antioxidant enzyme activities in mice. Glycyrrhizin (10) and β- glycyrrhetinic acid (11) are the major components of G. glabra believed to have immunomodulatory properties. β-glycyrrhetinic acid has a potent inhibitory activity on the classical complement
pathway (IC50 = 35µM), but it has no inhibitory activity towards the alternative pathway (IC50 >
2500µM) 47.
Hippophae rhamnoides L. (Elaeagnaceae)
Several reports have been made on immunomodulation of Hippophae rhamnoides L.
(Seabuckthorn) using different types of immunomodulatory models. Alcoholic extracts of leaves and fruits of H. rhamnoides at 500 µg/ml concentrations were found to inhibit chromium- induced free radical production, apoptosis, DNA fragmentation and restored the anti-oxidant status to that of control cells. The extract of leaf of H.
rhamnoides also reported to possesses immunomodulatory activity through cellular and humoral immune response. Administration of leaf extract at 100 mg/kg dose along with chromium (Cr) significantly inhibited Cr-induced immunosuppression. The extract significantly inhibited Cr-induced reactive oxygen species generation and maintained the cell size identical to that of control cells. Cr treatment markedly inhibited the mitochondrial transmembrane potential by larger lymphocytes in particular, while the leaf extract restored the same significantly. The leaf extract at 100µg/ml alone stimulated IL-2 and IFN-γ production even in the absence of concanavalin A and also inhibited Cr-induced decline in IL-2 and IFN-γ production but it did not change IL-4 production. The ethanolic extract and of H. rhamnoides fruit and its flavones fraction have been reported to stimulate the production of interleukin-6 and tumor necrosis factor- alpha (TNF-α) in peripheral blood mononuclear cells (PBMCs). The increased expressions of p-I κB, NF- κB and p-p38 were observed with flavones fraction of H. rhamnoides fruit extract in human PBMCs with significantly suppressed expression of CD2548.
Hydrastis canadensis L. (Ranunculaceae)
Hydrastis canadensis (Goldenseal) is indigenous to North America, and commonly used in conjunction with echinacea for the treatment of colds and flu.
Sevaral reports have been published for its immunomodulatory activity. Root extract of H.
canadensis showed antigen-specific in vivo immunomodulatory potential on rats that were injected with the novel antigen keyhole limpet hemocyanin.
Berberine (12) alkaloid is thought to be the potent immunomodulator present in H. Canadensis. Berberine suppressed experimental autoimmune tubulointerstitial
