Role of cytokines in bee venom therapy - Part I
By Ahmed Hegazi
Professor of Microbiology and Immunology
National Research Center , Dokki, Giza , Egypt
Member of Apitherapy Commission, APIMONDIA
E mail: ahmedgaffer@mailer.eun.eg and ahmedhegazi128@gmail.com
Apitherapy (the term comes from the Latin apis, which means "bee."), or bee therapy, is the use of honeybee venom for therapeutic purposes. Bee venom, bee pollen, raw honey, royal jelly, and propolis are products from bees that are generally considered to have medicinal effects. These products are effective against a wide range of ailments, from arthritis and chronic pain to multiple sclerosis and cancer, although few scientific studies have proved their benefits. The history of apitherapy extends back to ancient Egypt (Hegazi, 1998), China (Yu,.1999) and Greece . Apitherapy had been well documented in traditional Chinese medicine for treating systemic immune diseases, allergic diseases, viral diseases and organic-specific inflammatory diseases since more than one thousand years (Yu,.1999).
Bee venom (BV) has been used traditionally for the control of pain and inflammation in various chronic inflammatory diseases, including rheumatoid arthritis (RA) in Oriental medicine. Lee et al., (2004) evaluate the anti-inflammatory and anti-cytokine effect of BV on a murine type-II collagen-induced arthritis (CIA) model in male mice.
Cytokines (Greek cyto-, cell; and -kinos, movement) are a category of signaling molecules that are used extensively in cellular communication . They are proteins , peptides , or glycoproteins . The term cytokine encompasses a large and diverse family of polypeptide regulators that are produced widely throughout the body by cells of diverse embryological origin. (Gilman et al., 2001). Cytokines are small secreted proteins which mediate and regulate immunity, inflammation, and hematopoiesis.
Cytokine is a general name; other names include lymphokine (cytokines made by lymphocytes), monokine (cytokines made by monocytes), chemokine (cytokines with chemotactic activities), and interleukin (cytokines made by one leukocyte and acting on other leukocytes).
Bee venom (BV), well known as a traditional Oriental medicine, has been shown to exhibit anti-arthritic and anti-carcinogenic effects. However, the molecular mechanisms responsible for the anti-inflammatory activity of BV have not been elucidated in microglia. Moon et al., (2007) investigated the anti-inflammatory effect of BV and its major component, melittin (MEL), on lipopolysaccharide (LPS)-stimulated BV2 microglia. Their findings indicate that BV and MEL exert anti-inflammatory effects by suppressing the transcription of cyclooxygenase (COX)-2 genes and proinflammatory cytokines, such as interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha. These results demonstrate that BV and MEL possess a potent suppressive effect on proinflammatory responses of BV2 microglia and suggest that these compounds may offer substantial therapeutic potential for treatment of neurodegenerative diseases that are accompanied by microglial activation.
Bee venom (BV) has been used in patients with rheumatoid arthritis, a condition characterized by rheumatoid joint destruction mediated, in large part, by matrix metalloproteinases (MMPs). Nah et al., (2008) investigated the effects of melittin, a major component of bee venom, on the production of MMPs in human rheumatoid arthritic fibroblast-like synoviocytes (FLS). Mellitin had no effect on IL-1beta- or TNF-alpha-induced MMP1 or MMP3 production and did not decrease LPS-induced secretion of MMP1.
Among the serum proinflammatory cytokines, the production of TNF-alpha in the BV group was suppressed compared to the control group (59 +/- 4.5 versus 99.5 +/- 6.5, p < 0.05), but IL-1beta was not suppressed. Interleukin production and the in vitro mitogenic responses from honey bee venom treated normal rat splenocytes were reduced considerably compared to controls. Addition of interleukin-1 (IL-1) or interleukin-2 (IL-2) supernatants to these cultures in vitro resulted in an increase of their responses to normal levels. These results suggest that in vivo honey bee venom treatment affects the production of IL-1 by macrophages directly ( Hadjipetrou-Kourounakis and Yiangou, 1988) .
Data obtaind by Moon et al., (2007) indicated that BV and MEL exert anti-inflammatory effects by suppressing the transcription of cyclooxygenase (COX)-2 genes and proinflammatory cytokines, such as interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha. BV and MEL also attenuated the production of prostaglandin E(2) (PGE(2)). These results demonstrate that BV and MEL possess a potent suppressive effect on proinflammatory responses of BV2 microglia and suggest that these compounds may offer substantial therapeutic potential for treatment of neurodegenerative diseases that are accompanied by microglial activation.
Abd Raboo et al., (2008) found that Propolis and bee venom are effective in treatment of psoriasis, with minimal tolerable side effects, when used either separately or in combination. a significant reduction in both PASI score and serum level of IL-1β was observed in all groups of patients. Correlation between percentage reduction of PASI score and that of IL-1 β showed a strong positive correlation in group I received bee venom.
High dose bee venom exposure in beekeepers by natural bee stings represents a model to understand mechanisms of T cell tolerance to allergens in healthy individuals. Continuous exposure of nonallergic beekeepers to high doses of bee venom antigens induces diminished T cell-related cutaneous late-phase swelling to bee stings in parallel with suppressed allergen-specific T cell proliferation and T helper type 1 (Th1) and Th2 cytokine secretion. Meiler et al., (2008) found after multiple bee stings, venom antigen-specific Th1 and Th2 cells show a switch toward interleukin (IL) 10-secreting type 1 T regulatory (Tr1) cells. T cell regulation continues as long as antigen exposure persists and returns to initial levels within 2 to 3 mo after bee stings. Histamine receptor 2 up-regulated on specific Th2 cells displays a dual effect by directly suppressing allergen-stimulated T cells and increasing IL-10 production. In addition, cytotoxic T lymphocyte-associated antigen 4 and programmed death 1 play roles in allergen-specific T cell suppression. In contrast to its role in mucosal allergen tolerance, transforming growth factor beta does not seem to be an essential player in skin-related allergen tolerance. Thus, rapid switch and expansion of IL-10-producing Tr1 cells and the use of multiple suppressive factors represent essential mechanisms in immune tolerance to a high dose of allergens in nonallergic individuals.
Kim et al., (2008) found that bee venom. injected i.p at doses of more than 20 microl/100g mouse once a day for 14 days inhibited the ability of inguinal lymph node cells to produce T cell cytokines interleukin-1beta, -2, -6, tumor necrosis factor-alpha and interferon-gamma.
Histamine released from activated mast cells and basophils is an important mediator in allergy. Therefore, antihistamines are efficiently and widely used to suppress allergic symptoms. Johansen et al., (2008) evaluated the role of antihistamines in sensitization against allergens and in the efficiency of allergen-specific immunotherapy. The results demonstrated that sensitization against bee venom was strongly enhanced during treatment with antihistamines. Clemastine increased IgE production while decreasing IgG2a production against bee venom. This T-helper type 2 shift of the humoral response appeared to be caused by reduced IFN-gamma and enhanced IL-4 secretion from allergen-specific T cells. We also found reduced TNF-alpha, IL-6 and major histocompatibility complex class-II expression by macrophages. In sensitized mice, the efficiency of allergen-specific immunotherapy was reduced by clemastine treatment.
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