Mechanisms of action underlying the anti-inflammatory and immunomodulatory effects of propolis: a brief review-ReassuringHealthcare

Propolis

Mechanisms of action underlying the anti-inflammatory and immunomodulatory effects of propolis: a brief review

August 27,2022
by Kazi Eric Carter

Abstract

Many biological properties have been attributed to various types of propolis, including anti-inflammatory, antimicrobial, antioxidant, antitumor, wound healing, and immunomodulatory activities. This article reviewed studies published that investigated the anti-inflammatory activity of propolis of different origins and/or its isolated components, focusing on the mechanisms of action underlying this activity and also addressing some aspects of immunomodulatory effects. The search was performed of the following databases: PubMed, Science Direct, HighWire Press, Scielo, Google Academics, Research Gate and ISI Web of Knowledgement. The anti-inflammatory activity was associated with propolis or compounds such as polyphenols (flavonoids, phenolic acids and their esters), terpenoids, steroids and amino acids. CAPE is the most studied compounds. The main mechanisms underlying the anti-inflammatory activity of propolis included the inhibition of cyclooxygenase and consequent inhibition of prostaglandin biosynthesis, free radical scavenging, inhibition of nitric oxide synthesis, reduction in the concentration of inflammatory cytokines and immunosuppressive activity. Propolis was found to exert an anti-inflammatory activity in vivo and in vitro models of acute and chronic inflammation and others studies, indicating its promising potential as anti-inflammatory agent of natural origin and as a source of chemical compounds for the development of new drugs.

Mechanisms of action underlying the anti-inflammatory and immunomodulatory effects of propolis: a brief review

Marcio A. R. AraujoI, ; Silvana A. LibérioI; Rosane N. M. GuerraI; Maria Nilce S. RibeiroII; Flávia R. F. NascimentoI

ILaboratório de Imunofisiologia, Universidade Federal do Maranhão, Brazil

IILaboratório de Farmacognosia, Universidade Federal do Maranhão, Brazil

ABSTRACT

Keywords: anti-inflammatory activity, bee products, inflammation, propolis, propolis components

Introduction

Propolis is the generic name for a complex mixture of resinous substances collected from plants by bees, which is used in the bee hive to coat the inner walls, to protect the entrance against intruders, and to inhibit the growth of fungi and bacteria (Ghisalberti, 1979; Burdock, 1998). For propolis production, bees add their salivary enzymes to the plant resin and this material is then partially digested, followed by the addition of wax also produced by the bees. This process is found in most bee species. An additional step is observed in the group of stingless bees of the subfamily Meliponinae, species that are native to South America. In this group, resins, saliva and wax are mixed with soil to form the so-called geopropolis (Bankova et al., 1998).

The chemical composition of propolis is strongly influenced by the type of vegetation visited by the bees and by the season of the year (Bankova et al., 2000; Majiene et al., 2004; Daugsch et al., 2008; Teixeira et al., 2008). Propolis from temperate zones generally consists of 50-60% resins and balsams, 30-40% of wax, 5-10% of essential and aromatic oils, 5% of pollen, and 5% of other substances (Mendoza et al., 1991). These substances comprise more than 210 different compounds identified so far, such as aliphatic acids, aromatic esters and acids, flavonoids, fatty acids, carbohydrates, aldehydes, amino acids, ketones, chalcones, dihydrochalcones, terpenoids, vitamins (B1, B2, B6, C, and E), and minerals (aluminum, antimonium, calcium, cesium, copper, iron, lithium, manganese, mercury, nickel, silver, vanadium, and zinc) (Ghisalbert, 1979; Moreira, 1990; Marcucci, 1995; Sousa et al., 2007; Chang et al., 2008; Lustosa et al., 2008). Therefore variation in propolis components could affect its properties (Nakamura et al., 2010).

Propolis has been used since ancient times for the treatment of many diseases, as well as in food products and cosmetics (Burdock, 1998). In fact, various biological properties have been demonstrated and attributed to different types of propolis, including antibacterial, antifungal, antiprotozoal, antioxidant, antitumor, anti-inflammatory, anesthetic, wound healing, immunomodulatory, antiproliferative and anticariogenic activities (Dobrowolski et al., 1991; Ivanovska et al, 1995; Moura et al., 1999; Kujumgiev et al., 1999; Isla et al., 2001; Chen et al., 2004; Simões et al., 2004; Duran et al., 2006; Medic-Saric et al., 2009; Araujo et al., 2010; Sforcin, 2007; Libério et al., 2009; Pagliarone et al., 2009, Paulino et al., 2003).

This article reviewed studies that investigated the anti-inflammatory and immunomodulatory activity of propolis, focusing on the mechanisms of action (already identified) underlying this activity and on the components identified in the different types of propolis. The following databases were searched: PubMed, Science Direct, HighWire Press, Scielo, Google Academics, Research Gate and ISI Web of Knowledgement, for articles published between 1979 and 2011 using the key words propolis, inflammation, anti-inflammatory activity, bee products and propolis components.

Anti-inflammatory Activity

Chemical aspects of the inflammatory response

Inflammation is induced by the release of chemical mediators from damaged tissue and migratory cells. Mediators identified in the inflammatory process include vasoactive amines (histamine and serotonin), eicosanoids (metabolites of arachidonic acid, prostaglandins and leukotrienes), platelet aggregation factors, cytokines (interleukins and tumoral necrosis factor - TNF), kinins (bradykinin), and free oxygen radicals, among others (Czermak et al, 1998; Ohishi, 2000). These substances are produced by inflammatory cells such as polymorphonuclear leukocytes (neutrophils, eosinophils, basophils), endothelial cells, mast cells, macrophages, monocytes, and lymphocytes (Fiala et al., 2002).

It is well established in the literature that the main phenomenon activating the acute phase of inflammation is the local production of prostaglandins (especially PGE 2 ) and leukotrienes derived from arachidonic acid. These eicosanoids are relatively unstable and are notoriously non-selective in their interaction with various receptor subtypes as demonstrated in isolated tissue preparations (Coleman et al., 1994; Hata & Breyer, 2004).

Arachidonic acid is the precursor of eicosanoids such as prostaglandins. This fatty acid is stored as a phosphoglyceride in the cell membrane and is converted by cyclooxygenases or lipoxygenases. After tissue damage, conversion through cyclooxygenases leads to the synthesis of prostaglandins, which actively participate in the onset and progression of the inflammatory reaction. Studies have demonstrated that propolis acts as a potent anti-inflammatory agent in acute and chronic inflammation (Ledón et al., 1997; Uzel et al., 2005). Some of the substances present in propolis are able to inhibit cyclooxygenase and the consequent synthesis of prostaglandins (Sigal & Ron, 1994). This has been suggested to be one of the mechanisms of action underlying the anti-inflammatory effect of propolis. Still, molecules that exert lipoxygenase(LOX) inhibitory and antioxidant activities also have potential anti-inflammatory activity (Polya, 2003).

Anti-inflammatory and immunomodulatory response to propolis extracts

The anti-inflammatory properties of propolis and its subproducts have been studied in different models of acute and chronic inflammation, such as formaldehyde-induced arthritis and paw edema induced by PGE 2 , carrageenan or radiation (Dobrowolski et al, 1991; Park & Kang, 1999; El-Ghazaly & Khayyal, 1995), as well as in acute inflammation induced by zymosan (Ivanovska et al., 1995) and others (Table 1). In many of these studies propolis had an effect similar to that of anti-inflammatory drugs used as positive controls in the experiments.

In vitro and in vivo experiments using ethanol or aqueous extracts of propolis of different origins produced by different bee species are being conducted to confirm its anti-inflammatory activity. Some specific effects of the aqueous extract of propolis have been demonstrated, such as the inhibition of platelet aggregation, inhibition of prostaglandin biosynthesis in vitro, prevention of formaldehyde-induced paw edema and arthritis and inhibition of 5-lipoxygenase (5-LOX) activity (Dobrowolski et al., 1991; Khayyal et al, 1993; Massaro et al., 2011). In addition, propolis has shown in vitro free radical scavenging activity and a hepatoprotective effect on TNF-α-induced cell death (Banskota et al., 2000; Alencar et al., 2007). The ethanol extract of propolis has shown dose-dependent anti-inflammatory effects in models of carrageenan-induced paw edema, Freund's adjuvant-induced arthritis and foreign body-induced granuloma, effects on vascular permeability, and analgesic activity (Park et al., 1996). Additionally to its regenerative capacity, free radical scavenging is the main anti-inflammatory mechanism attributed to the ethanol extract of propolis (Krol et al., 1996; Pascual et al., 1994; Ichikawa et al., 2002).

In a study evaluating the anti-inflammatory activity of an ethanol extract of propolis on edema induced by carrageenan, dextran and histamine in mice, an oral dose of 650 mg/kg significantly inhibited the inflammatory process triggered by carrageenan and antagonized the edematogenic effect produced by histamine, but did not inhibit the inflammatory process induced by dextran. The dose administered had no toxic effects and the authors suggest that the extract exerted an anti-inflammatory effect similar to that of nonsteroidal anti-inflammatory drugs without causing damage to the gastric mucosa or other blood effects (Reis et al., 2000).

Fourteen commercial extracts of Brazilian propolis originating from different regions of the country were tested using a rat model of arachidonic acid-induced ear edema. Four of the extracts tested showed anti-inflammatory effects similar to those produced by indomethacin, with these effects varying significantly depending on the origin of the propolis sample (Menezes et al., 1999).

The effects of propolis extracts were investigated in other rat models of inflammation. The arthritis indexes were suppressed by oral treatment with 50 and 100 mg/kg/day of the extract. In carrageenan-induced paw edema, the ethanol extract of propolis 200 mg/kg single dose showed a significant anti-inflammatory effect 3 to 4 h after carrageenan administration. The authors concluded that the extract presented marked anti-inflammatory effects in both chronic and acute inflammation and suggest that the anti-inflammatory effects of propolis might be due to its inhibitory effect on prostaglandin production (Park & Kahng, 1999).

Propolis has been shown to suppress the production of lipoxygenase and cyclooxygenase during acute zymosan-induced peritonitis and to inhibit in vivo the elevated production of leukotrienes B4 (LTB4) and leukotrienes C4 (LTC4). However, oral administration of the extracts did not affect the ex vivo production of PGE 2 , but increased the production of leukotrienes and prostaglandins by peritoneal macrophages (Mirzoeva & Calder, 1996). Massaro et al. (2011) suggests a potential of cerumen (stingless bees propolis) for preventing the lipid oxidation of linoleic acid, thus protecting the integrity of cell membranes.

Propolis extracts can act on the nonspecific immune response by activating macrophages, inducing the release of hydrogen peroxide, and inhibiting the production of nitric oxide in a dose-dependent manner (Orsi et al., 2000). The latter it may be explained by the fact that propolis inhibits both inducible nitric oxide synthase (i-NOS) expression and the catalytic activity of i-NOS (Tam-no et al., 2006).

A significant inhibition of both the PGE2 levels and in the nitric oxide effects it was demonstrated. There was also a reduction in enzymes activation and in the level of IL-6 and other inflammatory cytokines. Furthermore, inhibition of the activation and differentiation of macrophages has been suggested as one of the possible mechanisms underlying the anti-inflammatory and immunological effects of propolis extract and of its water-soluble derivatives. These effects are the result of the action of flavonoids and other components present in propolis (Krol et al., 1996; Hu et al., 2005).

It was suggested that propolis extract possess antioxidant capacity in vitro conditions (Rebiai et al., 2011). Propolis antiradical and protective abilities against lipid oxidation are related to its high levels of polyphenol and flavonoid total levels. According Chaillou & Nazareno (2009) and Ikegaki et al. (1999), propolis showed high antioxidant activity by inhibiting the oxidation of the coupled reaction of β-carotene and linoleic acid. These last authors suggest that propolis also seems to inhibit hyaluronidase, an activity contributing to its anti-inflammatory and regenerative effects. Propolis with strong antioxidant activity also has high scavenging activity and contains large amounts of antioxidative compounds, such as caffeic acid, ferulic acid, caffeic acid phenethyl ester and kaempferol (Chen et al., 2004; Ahn et al., 2007, Kumazawa et al., 2004).

Studies investigating an aqueous extract of rosemary propolis in an in vivo model of chronic inflammation demonstrated that the extract suppresses the cell migration. However, the deposition of collagen was not affected, suggesting that the aqueous extract of propolis can be used to control the inflammatory response without compromising the tissue repair process. This activity was attributed to the high content of caffeic acid in the propolis extract (Moura et al., 2009).

In vivo pre-activation of macrophages by green propolis extract administered to rodents has been suggested to increase the production of nitric oxide after activation with interferon gamma (INF-Γ) and, consequently, to reduce the proliferation of lymphocytes (Sá-Nunes et al., 2003). The inhibitory effect of propolis on lymphoproliferation might be associated with the production of regulatory cytokines such as IL-10 and TGF-β (?Sforcin, 2007), as well as the anti-inflammatory/anti-angiogenic effects of propolis could be also associated with modulation of cytokine TGF-β1 ??Moura et al., 2011). Recent works has demonstrate that the propolis administration over a short-term to mice affected both basal and stimulated IFN-Γ? production, what may be related to its anti-inflammatory properties (Pagliarone et al, 2009; Orsatti et al., 2010; Missima et al., 2010).

The activation of macrophages and release rates of nitric oxide and hydrogen peroxide have been studied using an ethanol extract of propolis in stressed mice to evaluate the effects of propolis on stress-related immunosuppression. The results showed that propolis reduced nitric oxide production and potentiated hydrogen peroxide formation. The histological characteristics of the thymus, bone marrow and adrenal gland were found to be altered, but no histological alterations were observed in the spleen. The authors concluded that propolis-based products might be used for the treatment of stress (Missima & Sforcin, 2008). Thus, it was shown that ethanol extract of propolis inhibits the inducible nitric oxide synthase (iNOS) gene transcription through action on the NF-kB sites in the iNOS promoter in a concentration-dependent manner (Song et al., 2002).

An in vivo study has been conducted on healthy humans, for the first time reporting the effects of prolonged propolis supplementation on redox-status of human organism. The benefit of propolis use was shown in male population demonstrating reduction in free-radical-induced lipid peroxidation as well as increase in activity of superoxide dismutase. Further a decrease in malonaldehyde (degradation product of peroxidation of polyunsaturated fatty acids) concentration and increase in superoxide dismutase activity (first and most important line of antioxidant enzyme defense) were observed (Jasprica et al., 2007).

The antiulcer activity of Brazilian green propolis was demonstrated by the administration of hydroalcoholic extracts to animals with gastric ulcers induced by ethanol, by a nonsteroidal anti-inflammatory drug (indomethacin) and by stress. A reduction in gastric secretion was also observed. The results obtained were attributed to the presence of phenolic acids (caffeic acid, cinnamic acid, p-coumaric acid and ferulic acid) in the extracts. However, the mechanisms of action still need to be established (Barros et al., 2007; 2008). The alcoholic extract of propolis has been shown to promote the acceleration of ulcer healing in the oral cavity of rats, by reducing the time of ulcer epithelization and interfering with the quality and quantity of inflammatory cells (Gregio et al., 2005). Still, propolis increases the wound healing rate and reepithelialization of diabetic wounds in rodents. It also has additional roles in decreasing neutrophil infiltration and normalizing wound tissue macrophage influx (McLennan et al., 2008).

Recent studies show that the ethanol extract of propolis is also able to interfere with others mechanisms underlying on the inflammatory response like the activity of phosphatidylcholine-specific phospholipase C (PC-PLC), that plays critical roles in controls of vascular endothelial cell function, as well as in the p53 - a key protein in apoptosis signal transductions of this cells - and further levels of reactive oxygen species (ROS) (Xuan et al., 2011). The propolis is responsible for ERK1/2 (extracellular signal-regulated kinase 1/2) inactivation in endothelial cells that ultimately leads to angiogenesis suppression (Kunimasa et al., 2009).

Anti-inflammatory and immunomodulatory response to isolated propolis components

Different components of propolis have been studied to evaluate their therapeutic application. Flavonoids, phenolic acids like caffeic acid phenethyl ester (CAPE), and esters are the most biologically active compounds (Table 2) (Burdock, 1998; Daugsch et al., 2008; Baumann et al., 1980; Silva et al., 2007). These compounds exert multiple effects on bacteria, fungi and viruses and also present anti-inflammatory, antioxidant, immunomodulatory, wound healing, antiproliferative and antitumor activities (Machado et al., 2008; Pagliarone et al., 2009; Buyukberber et al., 2009; Jaganathan & Mandal, 2009; Medic-Saric et al., 2009; Pillai et al., 2010; Moreira et al., 2011; Lotfy, 2006).

The anti-inflammatory activity of propolis seems to be associated with the presence of flavonoids, especially galangin and quercetin. This flavonoids has been shown to inhibit the activity of cyclooxygenase and lipoxygenase and to reduce the levels of PGE 2 and the release and expression of the induced isoform cyclooxygenase-2 (COX-2) (Shimoi et al., 2000; Raso et al., 2001). Studies using animal models of acute and chronic inflammation showed that caffeic acid is essential for the anti-inflammatory activity of propolis since it inhibits the synthesis of arachidonic acid and suppresses the enzymatic activity of COX-1 and COX-2 (Borrelli, 2002). In addition, caffeic acid inhibits the gene expression of COX-2 (Michaluart et al., 1999) and the enzymatic activity of myeloperoxidase (Frenkel et al., 1993), ornithine decarboxylase, lipoxygenase, and tyrosine kinase (Rao et al., 1993). Caffeic acid also presents immunosuppressive activity, inhibiting the early and late events of T cell activation and the consequent release of cytokines such as IL-2 (Marquez et al., 2004) in an unspecific way of inhibition of ion channels (Nam et al., 2009). Chrysin, a flavonoid isolated from propolis, also seems to suppress the expression of COX-2 by inhibiting a nuclear factor for IL-6 (Woo et al., 2005).

In vivo studies on artepillin C, the main component present in propolis from south and southeast of Brazil, have shown that this substance inhibits the production of PGE 2 during peritoneal inflammation. This activity may explain, at least in part, the anti-inflammatory and antiedematogenic effects of artepillin C observed in carrageenan-induced paw edema and peritonitis. Inhibition of the production of nitric oxide and TNF has also been reported (Paulino et al., 2008). Further artepillin C was found to have strong antioxidant effects may be accounted for by additional effects of caffeoylquinic acid and other prenyl analogues (Nakajima et al., 2009; Mishima et al., 2005).

Caffeic acid phenethyl ester (CAPE), the most extensively studied and biological active component in propolis, inhibit cytokine and chemokine production, proliferation of T cells and lymphokine production, and thus results in a decrease in inflammatory process. The mechanism is through to be related to NF-ΚB signaling pathway (Natarajan et al., 1996; Wang et al., 2009; 2010). CAPE is a potent inhibitor of nuclear factor -ΚB (NFΚB) activation (Shvarzbeyn & Huleihel, 2011) and NF-ΚB inhibition may result in a reduced expression of COX-2, whose gene is NF-ΚB-regulated (Maffia et al., 2002) and in a potent NO inhibition by blocking the activation of INOS (Nagaoka et al., 2003).

Other studies have investigated the effects of propolis and of its polyphenolic components (e.g., flavonoids) on LPS-induced production of nitric oxide and on the expression of inducible nitric oxide synthase (iNOS) by activated macrophages (Song et al., 2002; Hämälänein et al., 2007). The most effective classes of polyphenolic compounds were flavonoids, especially isoflavones and flavones. In addition, eight compounds that were able to inhibit the production of nitric oxide and expression of iNOS were identified. Four compounds (genistein, kaempferol, quercetin, and daidzein) inhibited the activation of two important gene transcription factors for iNOS, signal transducer and activator of transcription 1 (STAT-1) and NF-kB, whereas four other compounds (flavone, isorhamnetin, naringenin, and pelargonidin) only inhibited NF-kB (Hämälänein et al., 2007). Another study showed that selected flavonoids, including fisetin, kaempferol, morin, myricetin, and quercetin, exhibited distinct antioxidant properties against different types of free radicals (Wang et al., 2006). These results indicate that flavonoids have different antioxidant and anti-inflammatory effects despite their structural similarity (Hämälänein et al., 2007; Wang et al., 2006). Some flavonoids stimulate macrophages stop further production of eicosanoids and destroy excess oxidants (Havsteen, 2002).

Ansorge et al. (2003) studied the effects of propolis and some of its components on basic functions of mitogen-activated immune cells of human blood, as well as on DNA synthesis and cytokines production in vitro. The authors detected the production of IL-1ß and IL-12 by macrophages, as well as the production of IL-2, IL-4, IL-10 and transforming growth factor beta (TGF-β). The results showed that propolis, caffeic acid, quercetin, hesperidin and other flavonoids strongly inhibited DNA synthesis and the production of inflammatory cytokines in a concentration-dependent manner. On the other hand, the production of TGF-β, a mediator of immunosuppression, was increased. These findings demonstrate that propolis and a number of its constituents exerts a direct regulatory effect on basic immune cell functions and can be considered an alternative natural anti-inflammatory agent.

Recently, studies have been published on the known biological activities of CAPE as well as on the activities of other compounds as well studied as Artepillin C than the discovery of new components isolated from propolis from different regions, showing perspectives on propolis and its individual components for medicine (Aviello et al., 2010; Salatino et al., 2011).

Conclusions

The anti-inflammatory activity attributed to propolis has been confirmed in numerous in vitro and in vivo animal studies using models of acute and chronic inflammation. These studies attributed this biological activity to different mechanisms according to the results obtained. Most researchers reported an action of propolis extracts on the enzyme cyclooxygenase, a trigger of the inflammatory process. Furthermore, effective anti-inflammatory activity of propolis was attributed to the inhibition of prostanoids, especially PGE2, and to the reduction of cytokines. Other mechanisms were also reported, such as an effect on inflammatory cell activity (cell migration, macrophage activation), reduction in nitric oxide synthesis, reduced enzymatic activity during the healing process, and inhibition of TNF.

This review highlights the potential use of propolis as an alternative natural anti-inflammatory agent in acute and chronic inflammation. It is believed that propolis acts through different mechanisms and that its polyphenolic components are responsible for this action. However, the biological properties of the propolis should not be considered a synergic effect among the various compounds, suggesting the need for isolation and identification of the various bioactive compounds responsible for its effects, and to better understand their mechanisms of action.

As stated here, there is increasing scientific evidence confirming the anti-inflammatory properties of propolis and/or its components. In this respect, most of the studies analyzed here leave something to be desired since they do not specify the type and origin of the propolis sample studied or even the compound isolated, nor do they report the genus of the producing bee species, since propolis may have very different chemical composition and actions according to these factors.

Disclosure statement

There are no competing financial interests.

Received 2 Mar 2011

Accepted 28 Jun 2011

The Role of Propolis in the Beehive

In between acting as teacher to Alexander the Great and writing his great works on ethics and philosophy, Aristotle (384–322 bc) found time to write the ﬁrst detailed natural scientiﬁc study of animals. This work included substantial and detailed references to the working of the honeybee. Aristotle’s great goal was to under stand the intimate workings of the hive and in particular the role of the ‘mother bee’ or, as we know it, the queen bee.

Aristotle recognised two types of propolis and had clearly arrived at a detailed understanding of their role and purpose. Conosis propolis, he tells us, is used by the bees to ﬁll cracks and holes in the hive, keeping out the light, weather and potential intruders such as spiders, ants and other insects which might wish to invade the warmth, shelter and food supply of the hive. Mitys propolis, on the other hand, was a richer, darker, more aromatic substance. This was used to narrow the entrance to the hive and was also used in the cell walls.

Ad Amiri, an Arab writing some years later, provides us with a revealing insight both into the way Aristotle worked as a scientist and into the use made of propolis. In his attempt to observe the bees at work, Aristotle built an observation hive made of glass. But the bees did not approve and refused to work until they had smeared the inside of the glass with a dark, sticky substance, a clear reference to the use of propolis to block out the light in the hive.

The Bees’ External Immune System?

The role of propolis in the hive is linked to a central conundrum. How does a colony of bees, usually of 50,000 or more, crowded into a virtually hermetically-sealed space, at a constant temperature of 35°C (95°F) and with moisture levels of 90 per cent, manage to survive? Surely these conditions are perfect for the growing of bacteria and the spreading of disease, and yet bees have not only survived but prospered in such conditions for millions of years. In many ways, conditions in the hive mirror conditions in the human body (the brood-rearing temperature is actually the same as our body temperature) and present similar problems—constant high temperature and levels of moisture. The answer for us humans is that we have our complex immune defence mechanism, while the bees use propolis.

Dramatic as this may sound it is hard to avoid the conclusion that propolis effectively provides a form of externalised immune defence mechanism for the beehive, fulﬁlling its role in a multitude of ways. It does this at times by using very simple, practical, structural mechanisms. At other times it involves highly complex, pharmacological processes, aspects of which are as yet not entirely understood.

Defending the City

The labyrinthine passageway into the hive, the entrance to the city, incorporates both mechanisms. The winding passageway is built entirely of propolis. It should provide the only entrance into the hive. Through it must pass all the bee trafﬁc between the hive and the outside world. Practically and structurally, by narrowing the entrance down with propolis the entrance can be defended by the— guard bees against intruders—mainly other bees, ants and other insects. But it defends the hive in another more subtle way. Being made out of resin, it also acts as a kind of sterilizing chamber through which all the bees must pass—a long, narrow and circuitous chamber which slowly cleanses the bees of bacteria as they move towards the heart of the hive and an environment which is recognised as the most sterile known in nature.

As we have seen from Aristotle’s observations the honeybee does not like to be exposed to the light. In the wild, bees will build their hives in protected spaces like hollow tree trunks, caves or crevices. In urban environments they may seek the safety of roof spaces, as they have done in my own home in North Yorkshire, or redundant chimneys as one colony did many years ago at the ofﬁces of the International Bee Research Association in Cardiff ! Propolis is used to seal up the unprotected sides of the colony, keeping out the light as well as providing protection from the weather and intruders.

In commercial hives bees seek to protect themselves in a similar way, sealing up any external holes in the hive and closing any internal gaps which may cause unhealthy draughts, for example between the frames and the hive walls. However, they also use propolis to create the right amount of air circulation in the hive by restricting or enlarging, according to need, ‘ventilation’ holes through which air can enter from outside.

Beekeepers groan when you mention propolis. For most of them it is not a valuable natural medicine but rather a huge nuisance which increases their work in managing the bees and collecting the honey, by ﬁrmly gluing all the moveable parts of the hive to each other and to the hive walls. We have already heard how some beekeepers have tried to breed this tendency out of the bees. With current demand for good-quality propolis running high perhaps they should be doing the reverse.

Inevitably, however, not all would-be intruders into the hive are deterred by the natural fortiﬁcation provided by propolis. Felix Murat3 tells us of one variety of bees, Apis ﬂorea, which has a particular problem with ants. These ants have worked out that they stand no chance singly against the bees guarding the hive entrance so they have evolved a counter-strategy. They gather en masse near to the hive and then swoop on the hive entrance. Some ants are stung to death by the guards but inevitably the sheer numbers of ants are able to overwhelm them. When this happens the ants enter the hive killing the queen and removing everything edible, including larvae, honey and other bees. Apis ﬂorea however, not to be outdone, has itself devised a countermeasure. The bees smear propolis all over the area surrounding the entrance to the hive, creating something resembling a giant ﬂy trap, or in this case ant trap. The invading ants stick fast in the propolis and can be more easily stung and killed. The dead ants are then coated with propolis and can remain effectively mummiﬁed, sometimes in heaps around the entrance to the hive, until they are consumed by the voracious larvae of the wax moth which lays its eggs in beehives.

Dealing with Invaders

Unfortunately, not all intruders are kept out of the hive. Bees and other insects as well as snails and small animals—frogs, mice and lizards—sometimes ﬁnd their way into the hive in search of warmth and food. In the case of smaller insects this is not too much of a problem. They can be stung to death and even physically removed. It is the demise of the larger intruders which provides the most graphic and symbolic illustration of how propolis protects the body of the hive from infection. In the case of a mouse, for example, the bees may be able to sting it to death but cannot hope to remove it. Left to rot, the dead mouse would present a serious bacterial problem within the hive. The colony responds to the threat with a rapid transfer of all available propolis to the site of the corpse where they proceed to cover every exposed surface of the dead mouse, ﬁnally giving it a top coating of wax. The mouse, like the ants caught outside the hive, is effectively mummiﬁed, sealed up within the hive. The process of decomposition is stopped, the corpse is no longer a threat to the colony.

The role of propolis at this macro level is mirrored on a micro level within the hive. When we come to look at the pharmaco logical properties of propolis we will see how bacteria in the hive are not simply destroyed or annihilated as they might be by synthetic antibiotics; rather, they are surrounded, neutralised and disarmed in the same way as the mouse is—a powerful metaphor of the relationship between the natural and the man-made.

A High-Tech Building Material

Perhaps the least-known but most intriguing aspect of the role of propolis in the hive is its use as a building material. In 1964 a Russian scientist, J. K. Leipus,4 worked out that 1 lb of beeswax honeycomb was capable of holding 25 lbs of honey which, in engineering terms, makes honeycomb a remarkable substance. The interlocking hexagonal cells no doubt contribute something to the honeycomb’s strength but he suggests it is propolis which enables the comb to carry the load it does. 90–95 per cent of the comb is made of beeswax while the remainder is composed of propolis. The propolis acts like a natural ‘carbon ﬁbre’ reinforcement both within the cell itself and in connecting it with surrounding cells. Leipus also demonstrated that all the brood cells and honey cells were coated with a very thin but complete layer of propolis resin. Apart from the sterilizing function of this lining the naturally impervious and adhesive tension of the resinous envelope probably also adds to the internal strengthening of each cell. It is interesting that resins are being incorporated in a new generation of building materials for the construction industry and that they are noted for their high-tensile and load-bearing properties. It seems once again that nature got there ﬁrst.

Sterilizing the Hive

Inside the hive, propolis is used in its most complex pharmaceutical form. A very ﬁne resinous material is used to ‘polish’ and effectively sterilize every surface in the hive. It is particularly important that the brood cells into which the queen will lay her eggs are bacteria-free. The queen bee can lay upwards of 3,000 eggs per day—over twice her own body weight. The worker bees ensure that every cell into which an egg is placed is lined with propolis. Ghisalberti,5 in his 1979 review of propolis, has suggested that an additional reason for coating the cells with propolis is to provide an impervious lining, limiting the escape of water vapour needed for the developing brood. Once the eggs have been laid, a wax and propolis mixture is used to cap each cell, providing a ﬁnal antibiotic and anti-fungal seal. Even the honeybee’s most determined bacterial enemy, Bacillus larvae—the cause of American Foul Brood,6,7 has been shown to succumb to propolis. The cells into which honey is stored receive a similar treatment— lined ﬁrst with propolis and then capped with wax and propolis. A traditional and highly effective remedy for bronchitis was for the sufferer to eat the comb cappings after the honey had been extracted.

One cannot help but marvel at the ingenuity and wisdom of the honeybee in the way it utilises propolis in so comprehensive and effective way within the hive.

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THE BUZZ ON BEES: The purpose of propolis – Campbell River Mirror

We have come to know honeybees (Apis mellifera) for what their name suggests: ‘honey bearing’. But honey isn’t the only product these pollinators create; honeybees are exceptional propolis manufacturers.

As beekeepers, we are all too familiar with propolis or ‘bee glue’- that sticky product that makes lifting the lid off the hive sometimes seem impossible. But what is propolis and why do bees encase their home with it?

Propolis is the by-product of tree resin, which honeybees collect from tree sap or leaf buds. Tree resin is collected on foraging flights. It is sticky, typically red in colour and attaches to the pollen sacs on the hind legs of worker bees. Once the worker bee arrives back at the hive, a fellow honeybee helps offload the sticky product which is then combined with several hive components, such as beeswax, honey and essential oils.

Why allocate foraging time and energy to collect a product that doesn’t feed the colony? Not only does this resin by-product hold structural integrity and aids in warding off wood decay, but it also acts as a defence against pathogens. Propolis properties are antibacterial and antifungal, and by encasing the colony in propolis, it creates an incredible natural defence barrier. In cases of insect intruders, the colony will sometimes kill the intruder and encase the body in propolis, protecting the colony from any spoils that the rotten carcass may release in their environment. In addition, in wild colonies found in hollow trees, you can sometimes see wood decay up to the propolis border protecting the colony – thus keeping their home pathogen-free and structurally intact. Propolis is undoubtedly an incredible product.

We can stimulate propolis production in our own hives by scraping the inside of the wooden boxes during hive construction. Scraping the wood will create the uneven texture honeybees tend to fill with propolis. In addition, when we do break this barrier during hive inspections, I would suggest refraining from scraping off this sticky substance completely. As you may notice, it takes quite a bit of energy to collect and manufacture enough propolis to seal every crack and unwanted entrance. By leaving propolis on the inner cover of your hive or between brood boxes, the sticky substance will easily reseal itself after your hive inspection is complete.

Happy beekeeping!

Rachel Halliwell is a Bee Master Certified beekeeper in the Comox Valley. Her website is

garden life

Mechanisms of action underlying the anti-inflammatory and immunomodulatory effects of propolis: a brief review