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Journal of Venomous Animals and Toxins

Print version ISSN 0104-7930On-line version ISSN 1678-4936

J. Venom. Anim. Toxins vol. 5 n. 1 Botucatu  1999 



E. VORONOVImage3233.gif (832 bytes), R. N. APTEImage3233.gif (832 bytes), S. SOFERImage3234.gif (837 bytes) Image3235.gif (888 bytes)

1 Department of Microbiology and Immunology, and 2 Pediatric Intensive Care Unit, Division of Pediatrics, Soroka Medical Center and the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.



ABSTRACT: Envenomation by insects, snakes, scorpions, and spiders involves the activation of the inflammatory system with the release and activation of pro-inflammatory cytokines, chemotactic mediators, cellular infiltration, and other vasoactive mediators. Activation of the inflammatory system and its cascade of events play a major role in the pathogenesis of envenomation, its clinical picture, and outcome. Additional clinical and laboratory studies are required to characterize the exact mechanisms by which the inflammatory system affects the pathophysiology, clinical course, and complications following envenomations. A better understanding of the involvement of the inflammatory cascade in different envenoming syndromes may have future therapeutic benefits.
Image3236.gif (882 bytes)KEY WORDS: Systemic inflammatory response, cytokines, pro-inflammatory cytokines, chemotactic mediators, vasoactive mediators.




Stings and bites by insects, spiders, scorpions, and snakes throughout the world cause significant morbidity and mortality in men. Clinical signs and symptoms following stings and bites vary significantly regarding the venom composition, amount of venom injected, age, size, and gender of the different species, as well as the geographical areas and seasons of the year. Other factors influencing the victims clinical picture and include their age or size (children are usually more severely affected), site of injection, and vulnerability to the venom (68,70,125,145,164,166). The analysis of snake venom has shown that it is a mixture of many toxic proteins and enzymes with diverse and complex pharmacological effects. Toxic substances may include neurotoxins, hemolysins, cardiotoxins, cholinesterases, and different phosphatases. The venom of a given species is usually predominantly neurotoxic (victims may die from respiratory paralysis) or necrotizing and it is frequently associated with hemolysis, bleeding, coagulopathy, myocardial dysfunction, and hemodynamic changes (112,115,116,164).

Scorpion venom contains mucopolysaccharides, hyaluronidase, phospholipase, serotonin, histamine, and neurotoxins. Neurotoxins are the most important components of the venom. These low-molecular weight polypeptides cause severe adrenergic and cholinergic activities and affect sodium, potassium, and chloride channels of various cells. The victims may exhibit signs and symptoms involving the central nervous system (CNS), stimulation of the autonomic nervous system, and occasionally, respiratory and heart failure, and even death (70,145).

Venoms of different species of spiders may be toxic to humans; the most important being the black widow venom which contains neurotoxins (latroxine) and may cause diffuse central and peripheral nervous excitement, autonomic activity, muscle spasm, hypertension, vasoconstriction, and even death due to cardiac or respiratory failure, mostly in children and the aged (166).

Numerous species of insects possess toxic venom, but by far, the most frequent and/or serious cases of envenoming are caused by hymenoptera. Venoms of hymenopterous insects (including bees, wasps, hornets, yellow jacket, and fire ants) contain enzymes, such as phospholipase A2 and hyaluronidases, small proteins and peptides, such as apamin and melittin, physiologically active amines, such as histamine, dopamine and norepinephrine, and amino acids. The usual reaction to a single sting is a sharp pain, local wheal, and erythema followed by intense itching. Hypersensitive individuals may develop anaphylaxis with urticaria, edema, bronchospasm, hypotension, coma, and death. Multiple stings may result in multisystem organ failure and death (68,125).

The components of different venoms may have direct toxic effects, inducing a local reaction or may trigger immediate hypersensitivity. However, when a person receives multiple stings, a severe toxic reaction mimicking anaphylaxis can usually develop (3). In addition to this hypersensitivity (IgE mediated), a delayed-type reaction mediated by T lymphocytes and their derived cytokines may develop.

In addition to specific signs and symptoms directly related to the venom toxic components, patients bitten by venomous snakes, hymenoptera insects, spiders, and scorpions may develop a systemic inflammatory response syndrome. There is also evidence of acute-phase reaction with hyperthermia or hypothermia, leukocytosis, neutrophilia, lymphopenia, eosinophilia, some clotting disorders, and protein imbalance with the increase of C-reactive protein and decrease of total proteins (15,146). Increasing evidence from animal studies and clinical experience shows that the involvement of the inflammatory cascade and release of cytokines play a major role in the pathogenesis of many envenoming syndromes.


GENERAL CHARACTERISTICS OF CYTOKINES: Cytokines are a diverse group of proteins of relatively low-molecular weight (rarely more than 8-25 kDa) with multiple functions (5,10,22,38,40,102,113,120). They regulate important biological processes, such as cell growth and differentiation, cell activation, inflammation, immunity, tissue repair, fibrosis, and morphogenesis. Although cytokines are considered to be a "family", this is a functional rather than a structural concept; these proteins are not all chemically related. Initially, cytokines were thought to be produced only by immune cells upon various insults, such as microorganisms and their products, antigens, cell-to-cell interactions, cytokines, and other environmental changes. Nowadays it is well accepted that other cells produce cytokines when challenged with various environmental or inflammatory insults, and these molecules are the soluble message of cell communications. The functions of cytokines are often redundant, and they can influence the synthesis and action of other cytokines, creating the "cytokine-network". Cytokines are effective at low concentrations (at a few pg/ml). This is due to their mode of action, involving binding to high-affinity receptors on the cell surface, which transmit cytokine signals to the nucleus. Cytokines often consist of a single chain and most cytokine receptors are made up of a single chain that binds to the cytokine, but does not contain signal transduction motifs. It has recently been reported that after binding of cytokines to their receptors, signal transducing chains are bound to this complex, initiating cell activation (75,79,150). In many cases, signal transduction chains are shared by numerous cytokines, and families of cytokine receptors have been characterized based on similarities in their extracellular domains.

The objective of this review is to discuss the cytokine network involved in the pathogenic effects that characterize envenomations following stings and bites. The active components of venoms, as mentioned below, induce pro-inflammatory cytokine production and tissue damage. Tissue breakdown products also stimulate pro-inflammatory cytokine production. Inhibitory cytokines, which exert negative effects on cells or inhibit the synthesis and function of other cytokines, have also been described and the net cellular response is determined by the cytokine network in the specific microenvironment. The role of inhibitory cytokines in limiting inflammatory and immune responses to envenomation is discussed below.


THE CYTOKINE NETWORK IN INFLAMMATION: Cytokines mediate all phases of the inflammatory responses and their network determines the outcome of these responses, an example being tissue damage versus healing. The macrophage is the cell most commonly associated with the initiation of tissue inflammatory responses. Three major cytokines interleukin-1 (IL-1), tumor necrosis factor a (TNFa), and IL-6 are of utmost importance in the mediation of inflammatory responses (5,9,10,37-40,65,113). Chemokines and other non-cytokine mediators also contribute to the inflammatory response (47,100,110,114,152). T helper cell cytokines are involved in the mediation of hypersensitivity reactions to venom components (77,144).


IL-1: IL-1 was previously known as a lymphocyte activating factor (LAF), endogenous pyrogen (EP), and catabolin. IL-1 is produced by monocytes/macrophages, but also by other cells, such as dendritic cells, some B cells, fibroblasts, epithelial cells, endothelium, and astrocytes. The main target cells for IL-1 are thymocytes, neutrophils, T and B cells, and various tissue cells. The main activity of IL-1 involves immunoregulation, mainly via T cell co-stimulation, activation of B cells, and inflammation including fever induction, acute-phase proteins, and tissue damage (10,37-40,102,113).

IL-1 consists of a family of two proteins, namely IL-1a and IL-1b, which overlap in their biological activities and bind to the same receptors (10,14,26,33,37,38) (40,81,97,102,113). However, IL-1a and IL-1b differ in the sub-cellular compartments in which they are active. IL-1b is active in its secreted form (17.5 kD), whereas its cytosolic precursor is inactive IL-1a is mainly active as an intracellular precursor (31 kD), or as a membrane-associated form (23 kD). being only marginally active in the secreted mature form (17.5 kD). IL-1 production is stringently controlled at multiple levels, such as transcription, translation, post-translation modifications, and also by its sub-cellular compartmentalization. IL-1 differs from most of the other cytokines by the lack of a signal sequence, and thus does not passing through the endoplasmic reticulum-Golgi pathway, resulting in the intracellular retention of the immature precursor forms. A cysteine protease called IL-1b-converting enzyme (ICE), which cleaves the inactive precursor of IL-1b to its active secreted form and is also involved in the apoptotic death of cells, was recently cloned and characterized (40,154). The processing of IL-1a is mediated by calpain, a calcium-dependent protease. Mononuclear cells manifest the strongest secretory capacity of IL-1a and IL-1b; IL-1b is secreted by phagocytic cells to a larger greater extent than IL-1a. Non-phagocytic cells secrete IL-1 only to a very limited level. IL-1 receptors (IL-1Rs), which belong to the Ig supergene family, are abundantly expressed on many cell types (14,26,33,39,40,81,97,143). The IL-1RtI is a signaling receptor, whereas the IL-1RtII serves as a decoy target, acting to reduce excessive amounts of IL-1.


TNFa: TNFa was first described as having toxic effects on tumors, inducing necrotizing effects mainly through influence on the tumor microvasculature. Later, it was found that the same mediator is also involved in weight loss (cachexia) seen in patients suffering from chronic parasitic diseases or advanced malignancies, and thus named cachectin (1,5,13,17,18,20,37) (57,102,111,155,158,160,161). Subsequently, the various pleiotropic effects on inflammatory responses and other cellular processes were reported. It is produced mainly by macrophages and lymphocytes and its main target cells are fibroblasts and endothelium. TNFb or lymphotoxin is a molecule related to TNFa and they both bind to the same receptors. TNFa is usually produced by activated macrophages, whereas TNFb is mainly produced by T lymphocytes activated by antigens. The activities of TNFb in inflammatory responses are more restricted, and for this reason, we will focus on TNFa. TNFa main actions include inflammation, catabolism (cachexia), fibrosis, production of other cytokines (IL-1, IL-6, GM-CSF), and induction of adhesion molecules. TNFa is initially synthesized as a nonglycosylated transmembrane protein of approximately 25 kD with a signal peptide. The orientation of membrane TNF is unusual, the amino terminus is intracellular, the transmembrane segment is near the amino terminus and the carboxy terminus is extracellular. A 17 kD fragment, including the carboxy terminus, is proteolyticaly cleaved off the plasma membrane of the mononuclear phagocyte to produce the "secreted" form, which circulates as a stable homotrimer of 51 kD. TNFa interacts as a homotrimer with surface receptors. The TNF family of receptors is subdivided into type I and type II. A key feature of this family is the presence in the extracellular domain of six cysteine residues ("NGF-R-like domains"). Other members of this family include Fas, CD40, and nerve growth factor (NGF). Some of the members of this family (p55 TNF receptor, Fas, and CD40) share a cytoplasmic domain called death domain, which is capable of transmitting cytotoxic effects.


IL-6: IL-6, previously known as a B-cell differentiation factor or hepatocyte stimulating factor, is produced by many cells including macrophages, T cells, B cells, fibroblasts, and endothelial cells (4,5,38,43,65,74,102,108). IL-6 is a 20 kD molecule which acts mainly on T cells, B cells, and hepatocytes, affecting B cell differentiation and antibody-forming cells (AFCs) and stimulating the production of acute-phase proteins in the liver. IL-6 is considered to be a growth factor for multiple myeloma, a malignancy of plasma cells. The IL-6 receptor belongs to the hemopoietin receptor family and consists of a single ligand binding chain. Following binding of IL-6 to the IL-6 receptor, the gp130 signal transducing chain, which by itself does not bind to IL-6, binds to the receptor. IL-6 binds to IL-6R with a relatively low affinity, but after the association with gp130, the affinity of this binding increases. Signaling through gp130 also characterizes other cytokines, such as IL-11, Leukemia inhibitory factor (LIF), and Oncostatin M (OSM) (16,36,150).


CHEMOKINES: Chemokines are small polypeptides (8-10 kDa) that are synthesized by several cells, such as phagocytes, endothelial cells, keratinocytes in the skin, fibroblasts, and smooth muscle cells of connective tissues, as well as T helper cells and platelets (47,100,110,114,152) All chemokines are related in amino acid sequence and function mainly as chemoattractants for phagocytic cells, most importantly recruiting monocytes and neutrophils from the blood to infection or injury sites. The activity of chemokines was also described in T cells and eosinophils. Members of the chemokine family are classified into three groups, as follows: CC chemokines with two adjacent cysteines (MIP-1b, MCP-1 or MCAF, and RANTES); CXC chemokines (IL-8, PBP/b-TG/NAP-2) in which the same two cysteines are separated by another amino acid; and C chemokines (lymphotactin and eotaxin) with only one cysteine residue present at the same site as in other chemokines (16,114). The three groups of chemokines act on different cell types: the CXC chemokines promote migration of neutrophils, while the CC chemokines promote the migration of monocytes; and the C chemokines, which have recently been identified, have individual specialized functions. Chemokines that promote chemotaxis of various T cell sub-populations or eosinophils have also been characterized. In many cases, chemokines also activate the function of their target cells. Thus, neutrophils activated by IL-8, as well as IL-1 or TNF, produce more oxygen radicals and nitric oxide and release their stored granule content, contributing to both host defense and local tissue destruction at inflammation sites. The chemokine receptors are coupled G-proteins which differ from other cytokine receptors by spanning the membrane seven times and displaying three extracellular and three cytoplasmic loops. Following ligand-receptor interaction, the G-protein associates with the cytoplasmic domain of the receptor and the G-protein a-subunit is activated, initiating the signaling pathway.


OTHER INFLAMMATORY MEDIATORS: In addition to cytokines, there are other important mediators that participate in inflammatory responses and allergic reactions that are relevant to venomous bites. These mediators are released by macrophages, and other tissue-resident cells, such as mast cells, neutrophils, eosinophils, basophils, lymphocytes, and platelets (16,34,36,51,66) (87,88,127,157,165). This group includes a variety of molecules, such as prostaglandins, oxygen radicals, nitric oxide (NO), thromboxanes, leukotrienes, particularly leukotriene B4 (LTB4), and platelet-activating factor (PAF). Plasma enzyme mediators are also important. Plasma contains four mediator-producing systems, such as the kinine system, clotting system, fibrinolytic system, and complement system. Following the activation of these systems, endothelial damage can induce activation of plasma clotting factors, resulting in vascular permeability, vasodilatation, neutrophil chemotaxis, and smooth-muscle contraction. The activation of the complement system, both by classical and alternative pathways contributes to the inflammatory mediators C5a (the most potent), C3a, and to a lesser extent, C4a. C5a, apart from being an inflammatory mediator by itself, also activates mast cells, inducing the release of their granule contents including histamine, serotonin (in mice), and LTB4. The detailed description of the contribution of non-cytokine mediators to inflammatory responses is beyond the scope of this review. However, it should be emphasized that these mediators cooperate with cytokines in the control of inflammation.



Alarm and secondary cytokines: As already mentioned, the cell most commonly associated with the initiation of tissue inflammatory responses is the macrophage (16,34,38-40) (64,87,88,113,157). Activated macrophages release a broad spectrum of cytokine and inflammatory mediators; the IL-1 and TNFa being of utmost importance for the initiation and propagation of the inflammatory process (35,39,40,101). At the inflammation site, other cellular events, such as mast cell degranulation and platelet aggregation and activation can also result in the release of mediators, which are chemotactic for macrophages and monocytes and activate their functions (128,130).

IL-1 and TNFa are especially important in initiating the next series of reactions (16,19,20,22,39,40) (51,66,87,101,113). As IL-1b is active in its secreted form, its effects on inflammatory responses are more widespread and prominent than those of IL-1a which is active in the cytosol or as a cell-associated form, (40). IL-1 and TNFa are considered as early or "alarm" cytokines with pleiotropic activities, acting both locally and distally. However, the most important activity of these cytokines is the induction in stromal cells (fibroblasts) of a second wave of cytokines. This amplifies the inflammatory signal and mediates the various phenomena that are seen in the inflammatory process. The cytokines of this second wave include IL-6, chemokines, IL-1, and TNF. IL-1 and TNF are also capable of inducing their own production. The synthesis of a wide array of non-cytokine inflammatory mediators is also induced by IL-1 and TNF in macrophages and other tissue-resident or stromal cells. IL-1, TNF, and IL-6 are considered the most important pro-inflammatory cytokines, as they produce a wide spectrum of biological activities that help coordinate the body responses to infection. Differences in their contribution to the inflammatory process will be mentioned below (1,4,5,10,17,18,20) (35,37,40,74,81,89,97) (101,102,108,143,149,154).

Pro-inflammatory cytokines induce local and systemic inflammatory manifestations. The local effects include the activation of vascular endothelium, increase in vascular permeability, and access of leukocytes into the affected tissue and their activation and local tissue destruction. The systemic manifestations include fever, the acute-phase response, and induction of a systemic shock in severe inflammatory processes.

Vascular effects and cell exudation: The first cytokine-mediated inflammatory manifestations include the dilatation and leakage of blood vessels, particularly the post-capillary venules. This results in tissue edema and, in some cases, red-cell extravasation, manifested by tissue redness. IL-1 and TNF stimulate blood flow, increasing vascular permeability and endothelial adhesiveness for white blood cells and platelets (1,5,10,13,16-18,20) (37,40,81,97,143,149,154). Local release of cytokines leads to an influx of fluid, cells, and proteins that participate in host defenses at the inflammation site. Later the small vessels clot, preventing the spread of infection or inflammation in the blood and the residual fluid drains to regional lymph nodes, where an adaptive immune response is initiated. In addition, IL-1 and TNF-induced low molecular-weight mediators released by the inflamed tissue, including reactive oxygen species, nitrous oxide, and metabolites of arachidonic acid, such as thromboxanes, prostaglandins, and leukotrienes contribute to the vasoconstriction and vasodilatation of the blood vessels. Local effects of inflammation caused by the release of histamine, serotonin, and platelet-activating factor also contribute to these vascular effects (16,19,27,36,51,66) (80,87,89,93,136,149).

Leukocyte exudation and accumulation at the inflammation site involve changes in the adhesion patterns of leukocytes to endothelial cells, ultimately resulting in a tight binding of leukocytes to endothelial cells and their migration into the inflamed tissue. IL-1 and TNF induce the expression of adhesion molecules, such as the intercellular adhesion molecule 1(ICAM-1) and the vascular intercellular adhesion molecule 1(VCAM-1) on endothelial cells, which bind with high affinity to their counter receptors on leukocytes, leukocyte function antigen-1 (LFA-1) and the very late antigen-4 (VLA-4), respectively. The interaction of these adhesion molecules arrests the rolling of leukocytes and induces a tight binding between leukocytes and endothelial cells, allowing them to squeeze between the endothelial cells and extravasate into the affected tissue (2,19,21,27,41,50,71,123,124,148).

IL-1 and TNF also induce the secretion of chemokines by endothelial cells, which further recruit leukocytes to the inflamed site and amplify the inflammatory response (1,5,10,13,17,18,20) (37,40,81,97,143,148,154). Chemokines produced by endothelial cells bind to proteoglycan molecules, both in the extracellular matrix and on endothelial cell surfaces, exhibiting the chemokines on a solid substrate along which leukocytes can migrate. Thus, the role of chemokines in cell recruitment is twofold: to bind to their receptors on leukocytes converting the initial rolling interaction of the leukocytes with endothelial cells into stable binding, and to direct leukocyte migration along a gradient of the chemokine that increases in concentration towards the inflamed site.

Once the leukocytes cross the endothelium and the basement membrane to enter the tissues, their migration to the site of the injury or infection is directed by the gradient of matrix-associated chemokines. As already mentioned, chemokines are produced by a variety of cell types in response to bacterial products, other pathogens and agents that cause physical damage. The ability of some chemokines, such as IL-8 and MCAF to activate the function of their target cells is also very important (47,99,100,110).

Another important aspect of the effects of IL-1, TNF, and IL-6 on cell mobilization into the injured tissue involves their distal effects on the bone marrow endothelium with the release of neutrophils into the blood that will subsequently migrate, at an enhanced rate, to the inflammation sites. Pro-inflammatory cytokines stimulate leukocytosis and the egression of cells into the relevant tissues (5,10,18,20,37,40,65).

After entering the inflamed tissue, leukocytes are again activated by cytokines, predominantly IL-1 and TNF, and to a lesser extent, by IL-6. As a result, they start to secrete a whole array of cytokines and inflammatory products, which subsequently amplify the response. This also applies to endothelial cells, as mentioned above. Thus, due to the cytokine cascade that is initiated and propagated by IL-1 and TNF, many cell types may be involved in the inflammatory response.

Fever induction: IL-1, TNF, and IL-6 are endogenous pyrogens, raising the body temperature that is believed to help eliminate infections (5,10,16,18,37,40,65) (80,83,87,88,93,127). Fever is induced by the effects of these cytokines on the thermoregulatory center in the hypothalamus. The cytokine-induced prostaglandin E2 (PGE2) is the second messenger of fever induction. The effects of IL-1, TNF, and IL-6 on muscle and fat cells also contribute to fever induction by altering energy mobilization and increasing body temperature. Most pathogens grow better at lower temperatures, and immune responses, such as the processing of antigen are more intense at higher temperatures. At later stages, the effects of IL-1, TNF, and IL-6 on the activation of T and B cells, which together with enhanced processing of antigen, increase the adaptive immune response.

The acute phase response: The liver is the main target of inflammation and the source of essential metabolites that the body needs to overcome stress (16,34,36,51,66,80,83,87,88,127). It also supplies the necessary components for immediate defense at the site of tissue damage, as well as confining tissue destruction, eliminating harmful agents, and aiding tissue repair. The liver response is also characterized by significant changes in the transport of ions and metabolites, the activities of most metabolic pathways, and the coordinate stimulation of the acute-plasma proteins (APPs). This involves a shift in the proteins secreted by the liver into the blood plasma and is the result of the action of IL-1, TNF, and mainly IL-6 on hepatocytes (4,13,16-18,20,34,37,40,52,57) (66,83,87,89,93,111,149,155,158,160). In the acute-phase response some plasma proteins decrease, while the levels of others markedly increase. The precise function of the acute-phase response is unknown. The increase in opsonizing proteins and anti-proteinases is believed to aid natural immunity and protect against tissue injury, respectively. Direct opsonins enhance the phagocytosis of microorganisms or tissue breakdown products. The C-reactive protein (CRP) binds to the phophorylcholine portion of certain bacterial and fungal cell wall lipopolysaccharides. When CRP binds to bacteria, it opsonizes them, but also activates the classical complement cascade by binding to C1q. The second APP of interest is mannose-binding protein (MBP). MBP is a calcium-dependent sugar binding protein or lectin, a member of collectins family (139). MBP binds to mannose residues on many bacteria, acting as an opsonin. Its structure resembles that of C1q of the complement system, and similar to C1q may activate a proteolytic enzyme complex that cleaves C4 and C2 to initiate complement activation. CRP and MBP do not bind to mammalian cell membranes, as phosphorylcholine in membrane phospholipids is in a form that does not react with CRP, whereas mannose residues on mammalian cells are covered with other sugars and cannot bind to MBP. CRP and MBP have the functional properties of antibodies, such as enhancing phagocytosis as they can bind to a broad range of microorganisms, providing defense mechanisms within a day or two after the initiation of injury or infection before specific immunity develops.

Protease inhibitors (a1-antitrypsin, a1-antichemotrypsin, a1-antiplasmin, and plasminogen activator inhibitor I) neutralize lysosomal hydrolases released from macrophages and neutrophils and limit tissue damage.

Pro-inflammatory cytokines are the major inducers of APP synthesis, mainly through the activation of gene transcription in the hepatocytes. Therefore, pro-inflammatory cytokines operate in a hormone-like manner, being generated at the inflammation site and transported to the liver via the bloodstream. IL-1, TNF, IL-6, and other cytokines and growth factors are strong inducers of APP synthesis, but the physiological significance of this phenomenon is not clearly understood.

In conclusion, the early activation of macrophages, with some contribution of platelet aggregation, and the secretion of alarm cytokines (IL-1 and TNF), result in all the local manifestations of the inflammatory response.


DIFFERENCES IN THE PRO-INFLAMMATORY POTENTIAL OF IL-1, TNF, AND IL-6: IL-1 and TNF are generally considered to mediate all aspects of inflammation, including the deleterious aspects, whereas IL-6 mainly mediates the beneficial effects of the inflammatory process (40,65,71,155,161). IL-1, TNF, and IL-6 induce fever, hepatic APPs, and T and B cell activation, whereas IL-1 and TNF also induce the synthesis of tissue-damaging substances, such as cytokines, inflammatory products (PGE2, PAF, nitric oxide etc.), and proteolytic enzymes (collagenase, plasminogen activator etc.) in leukocytes (mainly macrophages), stromal cells, and tissue-resident cells. The effects of IL-1 and TNF on endothelial cells, synovial cells, osteoclasts (bone), chondrocytes (cartilage), muscle cells, fibroblasts, and epithelial cells are well established.

Since IL-1 and TNF are pleiotropic, they can activate inflammatory processes at low concentrations. In fact, it is sometimes difficult to detect systemic IL-1 and TNF in the serum, while IL-6 levels are quite abundant. IL-6 levels are usually indicative of IL-1 and TNF production, as IL-6 is induced by IL-1 and TNF rather than by direct effects of inflammatory stimuli.

When generated locally in excess and for extended periods, IL-1 and TNF, but not IL-6, can induce local tissue damage. When there is a systemic infection or sepsis with bacteremia, which elicit TNF and IL-1 production at high levels, these cytokines act on all small blood vessels systemically, similarly to their local effects. This causes shock, disseminated intravascular coagulation (DIC) with depletion of clotting factors and consequent bleeding, multiple organ failure, and death. The hierarchy of IL-1 and TNF in mediating various inflammatory manifestations is still controversial. Experimental models of septic shock have demonstrated that after LPS injection, TNF appears first in the serum and then mediates the production of both IL-1 and IL-6 (4,18,20,22,37,38,40,57) (65,89,102,111,149,155,158,160).


RESOLUTION OF INFLAMMATORY REACTIONS: The net amount of pro-inflammatory cytokines, especially the "alarm cytokines" (IL-1 and TNF) and the duration of their secretion determine the nature of the inflammatory response. Low amounts of cytokines usually result in local inflammation, while high amounts of IL-1 and TNF may result in septic shock and death (4,18,20,22,37,38,40,57) (65,89,102,111,149,155,158,160). The generation of local low-moderate amounts of IL-1 and TNF for extended periods also contributes to the pathogenicity of autoimmune processes, as in rheumatoid arthritis and other organ-specific autoimmune diseases.

It is noteworthy that pro-inflammatory cytokines, especially IL-1 and TNF, also participate in tissue repair and wound healing. These cytokines stimulate cells (phagocytes, fibroblasts, chondrocytes, and other stromal cells) to generate and secrete degradative enzymes, such as metalloproteinases necessary to mediate tissue remodeling for subsequent phagocytosis by tissue macrophages also stimulated by IL-1 and TNF. In addition, IL-1 and TNF stimulate fibroblast proliferation and deposition of extracellular matrix constituents (ECM), contributing to scar formation (4,18,20,22,37,38,40,57) (65,89,102,111,149,155,158,160).

Acute inflammatory responses are usually limited by the decay in the initiation events, i.e., clearance of the pathogen or damaged tissue, which usually also results in the cessation of synthesis of pro-inflammatory cytokines. In addition, there are inflammation-mediated mechanisms, which actively suppress pro-inflammatory cytokine synthesis. IL-1 and IL-6 act on the adrenal-pituitary axis to generate adrenocorticotropic hormone (ACTH) that induces the production of cortisol which inhibits cytokine gene expression (44,98,129). Other mechanisms, which in turn inhibit the production pro-inflammatory cytokine, include physiological molecules that inhibit the function of pre-formed cytokines, i.e., soluble receptors and other inhibitors (1,4,11,13,22,33,37,38) (40,65,96,97,102,108,155,158,160,161). The IL-1 receptor antagonist (IL-1Ra) (22kD) is of special interest as a physiological inhibitor that binds to IL-1 receptors (IL-1R) without inducing agonistic effects. It is produced by several cells usually in conjunction with IL-1, functioning as a natural inhibitor. It has recently been shown that IL-1Ra fails to bind to the IL-1 receptor accessory protein (IL-1RAcP), a signal transducing chain that binds to complexes of IL-1 bound to its receptor, and thus fails to transmit the activation signal. Soluble cytokine receptors, which limit the amount of IL-1 and TNF in the various microenvironments in the body, have been characterized. Soluble receptors may originate from proteolytic cleavage of cell surface receptors or from alternative splicing of receptor encoding mRNAs. Interestingly, IL-1, one of the two types of receptors for IL-1, acts as a decoy target binding to IL-1 but not leading to signal transduction (40,81,96). Disturbances in the ratio between the cytokine and its natural inhibitors have been characterized in various pathological cases, such as IL-1 and TNF in septic shock and chronic inflammatory diseases (i.e. RA) (1,11,33,37,40,161). In these pathological conditions, excess of the cytokine in comparison to its natural inhibitors is observed. In addition, anti-inflammatory cytokines, such as IL-4 and IL-10, IL-13 and TGFb inhibit the production of pro-inflammatory cytokines (69,75,104,121,133,135,140). These cytokines are mainly generated by TH2 cells, as shown below, as well as by macrophages, and other stromal cells.


HYPERSENSITIVITY RESPONSES: Hypersensitivity responses to allergenic substances in venoms are the most common pathological manifestations of venomous bites. These IgE-dependent responses are controlled by TH2 cells, which secrete cytokines that control IgE production (120,132,142,163). Today it is well accepted that there are two major sub-populations of TH cells that differ in their differentiation pathways and effector functions. The sub-populations of TH cells differ mainly in the repertoire of cytokines that they secrete in response to antigenic stimulation. TH1 cells secrete mainly IFNg, IL-2, and TNFb. These cells are responsible for macrophage activation, which is of special importance for the eradication of intracellular parasites. T helper cells are also involved in the cultivation of cytotoxic T cells (104,121,133,135,140). TH1 cells also induce the transient production of IgG2a opsonizing antibodies. TH2 cells secrete cytokines that mediate humoral immunity mainly IL-4, IL-5, and IL-6 (but also IL-10 and IL-13). TH2 cells are important in the defense against extracellular parasites, which are mainly eradicated by neutralizing antibodies. These cells induce marked and long-lasting antibody responses, including the induction of the IgE and IgA switch (32,53,121,132,134) (135,138,142,163). Cytokines of TH2 origin also induce the accumulation and activation of mast cells and eosinophils in the tissues. TH2 responses are anti-inflammatory, since they inhibit the generation of pro-inflammatory cytokines, especially IL-1 and TNF by macrophages (32,53,120,121,126,132) (133-135,138,140,142,163). This is due to IL-4, IL-10, IL-13, and IL-6, which exhibit anti-inflammatory functions. These polarized responses of TH cells are best manifested in strong immune responses, especially against microorganisms. The irreversible differentiation of TH cell precursors into TH1 or TH2 cells depend on the conditions of priming of the precursors to the antigen. Antigen presenting cells (APCs) and cytokines produced by them are detrimental for the differentiation to TH cell precursors. IL-12 is the major cytokine that stimulates differentiation towards TH1 cells. IL-12 production by APCs during the antigen processing and its main function in TH1 differentiation includes the activation of NK cells to produce large amounts of IFNg that drives the differentiation of TH cell precursors. Other cytokines of APC origin, such as IL-1, TNFa, IFNa and TGFb synergize with IL-12 in IFNg induction. TH cell precursors differentiate into TH2 cells in response to IL-4. However, it is not yet clear which cell type secretes IL-4 needed for this priming event (53,120,121,126,133) (134,135,138,140,141). Candidates for IL-4 production are mast cells and a small cell population of T cells that express markers of both T and NK cells. As well as cytokines, other factors, such as the nature of the antigen, the dose, the protocol and route of immunization, and the genetic responsiveness of the host may affect the polarization of TH cell responses. There is a reciprocal cross-regulation of TH cell subsets mediated by cytokines, which they secrete. IL-4 inhibits the priming of TH cell precursors into TH1 cells and also inhibits the function of mature TH1 cells. This also applies to the inhibitory effects of IFNg on TH2 cells. As it has already been shown, the differentiation of TH cell precursors into one of the subsets is irreversible; memory TH cells retain their pattern of cytokine production upon challenge with the sensitizing antigen. Shifting patterns of TH cell differentiation represents a new therapeutic trend to prevent unwanted immune manifestations. For instance, in allergic responses one would try to inhibit IL-4 production/function or treat patients with IFNg to inhibit TH2 cells and promote the development of TH1 cells (72,92,159).


INSECT STINGS: Stings by bees and wasps can cause systemic reactions, which can be fatal for some individuals. It is estimated that 0.3%-3% of the population suffer from insect allergies (45,52,77). The pathophysiologic events following envenomation by hymenoptera stings have been extensively investigated. It was found that components of the insect venom may have direct toxic effects or may cause sensitization, and then result in allergic reactions to subsequent stings (103). Clinical manifestations of insect stings range from local reactions, such as itching, urticaria, angioedema to slight generalized symptoms with headache, fatigue, vertigo, and even life-threatening reactions. In the venom-sensitive patients, specific IgE to the venom is produced and participates in immediate hypersensitivity reactions (atopic allergy), which occur within seconds or minutes after venom inoculation. Delayed-type hypersensitivity reactions may also develop some days after the sting. This latter reaction is mediated by T cell responses and is manifested as local erythema, induration, and dermatitis. T cells and their derived cytokines contribute to the control of the immune responses against venom components (72,73,92,120). Bee venom consists of various components including acid P, melittin, apamin, hyaluronidase, PLA2, and peptide 401. PLA2 which is the major allergen, has three peptide and glycopeptide T cell epitopes (31,162). Over 90% of the patients with bee-venom anaphylaxis have an IgE-antibody response to PLA2 (76,106,147). PLA2 can elicit both IgE mediated allergy and normal immunity to bee stings, which are generally associated with high affinity IgG4 anti-PLA2. It is not completely understood why severe allergic reactions to insect stings develop in only a small number of exposed individuals. However, a significant difference in T cell responses to venom antigens was found when comparing allergic and non-allergic individuals (23,25). Very low concentrations of IL-3, GM-CSF, and IL-5, but not IL-8 and CSF-1, can induce a significant degranulation of basophils in response to the antigen. The venom can stimulate TH2 cells to produce IL-4, IL-5, IL-6, IL-10, and small amounts of IFNg, IL-2, IL-3, TNF-a and IL-12 can also be induced by venoms (3,28,29,92). In spite of low or undetectable production of IFNg by allergen specific TH clones following stimulation with a low concentration of antigens, these TH clones are capable of generating significant amounts of IFNg after optimal activation through their T cell receptor. IFNg is clinically relevant to allergy, as it inhibits TH2 immune responses and acts as a negative regulator of IgE production (32,46,53,120,121) (133,135,138,140). Allergen specific TH clones isolated from allergic individuals required higher doses of antigen to reach the plateau of proliferation and to generate TH0 cytokine responses than their counterparts isolated from non-allergic subjects. When allergen was replaced by anti-CD3 monoclonal antibodies, both allergic and non-allergic TH clones proliferate with significant IFNg production. These results are comparable with the high expression levels of IFNg mRNA in people allergic to wasp stings (25).

Melittin, another component of bee venom, is a 26-residue peptide known to damage cell membrane enzyme systems (60 ). Melittin works synergistically with PLA2 on many biological membranes, causing myonecrosis, necrosis of skeletal muscle cell, and lysis of erythrocytes (115,117). Melittin has also shown to mimic both the cytotoxic and mitogenic actions of TNF (119).

Bomalaski et al. (24) found that a mammalian protein (Phospholipase A2-activating protein-PLAP) has a structural similarity to melittin and activates PLA2, and can also induce the synthesis of TNF-a and IL-1 (144). Hence, the PLA2 enzyme is a potent inducer of IgE antibodies and can also cause a non-immunological degranulation of mast cells. It has previously been shown that PLA2 may induce mast cell activation (109). At the same time, IgE can induce direct mediator release by mast cells with de novo synthesis and secretion of IL-4 (42). Machado et al. (91) described a mouse model in which the initial enzymatic activation of mast cells and basophils led to IL-4 production. In a paracrine way, IL-4 led T helper cells to TH2 differentiation, and ultimately induced B cell activation with production of IgE. The enhanced production of TH2 helper cytokines by allergen-specific TH cells plays a major role in the induction and maintenance of IgE-mediated allergic disorders. Aggregated IgE can also be bound to high-affinity receptors on the surface of basophils and mast cells, playing a central role in inflammatory and immediate allergic reactions, and in degranulation and the release of many potent inflammatory mediators, such as histamine, proteases, chemotactic factors, and metabolites of arachidonic acid and cytokines (55,56,61). Mast cells play an important role (91) both in IgE-dependent and IgE-independent responses. These short-lived mediators have rapid effect. However, the activation of other mast-cell enzymatic pathways leads to the generation of other vasoactive substances, such as leukotrienes and other metabolites of arachidonic acid. Mast cells also synthesize and secrete a variety of cytokines including IL-3, IL-4, IL-5, and TNFa that can prolong the allergic reaction. The mediators and cytokines released by mast cells cause an influx of monocytes, T cells, and eosinophils into the sting site, causing a late-phase reaction (6-12 hours after the sting) dominated by a cellular infiltrate. Activated macrophages release a broad spectrum of mediators, such as IL-1 and TNFa, both playing an important role in this allergic reaction. As already mentioned above, these early cytokines have pleiotropic activity and act both locally and systemically on the immune and inflammatory responses. These can induce a cascade of events leading to the release of other cytokines from fibroblasts and endothelial cells at the inflammation site that may cause cell destruction and tissue necrosis. In studies of cytokine expression after endotoxin challenge, TNFa and IL-1 were found in the circulation within minutes after PLA2 expression. IL-4 appears to play a significant role in modulating acute inflammation and allergic reactions. IL-4 can cause the downregulation of pro-inflammatory cytokines, release of PGE2, and upregulation of IL-1Ra (53,120,121,133,135,138,140). At the same time, IL-4 can also enhance apoptosis of monocytes, thereby leading to a reduced accumulation of these cells in the tissues (95).

TNFa and IL-4 produced by mast cells can modulate adhesion molecules on endothelial cells, such as ICAM 1, ELAM-1, VCAM-1, and expression of some integrins on basophils and mast cells (54,61,63). They can also modulate the adhesiveness, migration, proliferation, and secretory function of these cells after the initiation of the local reaction. The synthesis of IgE antibodies largely depends on IL-4 and can be suppressed or augmented by IL-12 in a dose-dependent manner (enhancement of IgE production after low doses of IL-12 and temporary reduction of antibodies after high doses) (3,53,120,121,133,135,138,140). These results demonstrate the various effects of cytokines on ongoing immune response in vivo (49).



Local necrosis: Similar to the pathogenesis of insect envenomation, the mechanism for local tissue destruction due to snake envenomation involves activation of the cellular immune response in which the cascade of events is usually initiated by tissue macrophages and blood monocytes. As already mentioned, activated macrophages release a broad spectrum of mediators, of which cytokines like IL-1 and TNFa play an important role (35,39,40). These can induce the formation of other cytokines from local fibroblasts and endothelial cells at the envenomation site, for instance, IL-8 and platelet-activating factor (131,149). As mentioned above, this can augment the homeostatic signals and initiate the cellular and cytokine cascades involved in the complex process of local inflammatory reaction.

Snake venom contains high amounts of zinc metalloproteinases with a high degree of similarity to matrix metalloproteinases (118). Moura-da-Silva et al. (105) reported that venom metalloproteinases can cleave pro-TNFa into its mature form, and this is one important mechanisms of venom-mediated necrosis (48). Two venom zinc metalloproteinases from the snakes Bothrops jararaca and Echis pyramidum leakeyi were shown to be capable of cleaving the recombinant GST-TNFa substrate to a form biologically active TNFa (84). The application of anti-TNFa antibodies results in a reduction of venom-induced necrosis in mice injected with Echis pyramidum leakeyi venom. These observations demonstrate the importance of TNFa in the formation of necrotic lesions. This observation led to the hypothesis that increased levels of venom metalloproteinases following snakebite release active TNFa, promoting the generation of endogenous matrix metalloproteinases, resulting in a positive feedback mechanism with repeated cleavage of pro-TNFa. A direct cytotoxic effect was demonstrated of hemorrhagic metalloproteinase bilitoxin from Akgistrodon bilineatus venom on muscle fibers (115,116). Hemorrhagic toxins (including metalloproteinases) induce necrosis at the bite site damaging small vessel integrity (58,59). The pathogenesis of the hemorrhagic effects induced by the metalloproteinase BaP1 from Bothrops asper venom was investigated (137). It was shown that intramuscular injection of BaP1 into mice induced rapid hemorrhage in muscular and adipose tissues and hydrolysis of type I and IV collagen, fibronectin and laminin on in vitro incubation of BaP1 with muscle tissue. It has been suggested that the hemorrhagic effects induced by BaP1 are due to the proteolytic degradation of the basement membrane of small vessels and that disruption of endothelial cells may be a secondary event. BaP1 is involved in local tissue damage by induction of hemorrhage, myonecrosis, inflammation, and extracellular matrix alterations.

In summary, it can be concluded that the extent of local necrosis after snakebite is markedly affected by the release of cytokines, such as TNFa and IL-1 induced by the venom metalloproteinases. Subsequently, the cytokines activate the endogenous metalloproteinases in various cells (fibroblasts), which can cleave TNFa and amplify the process of cell destruction and necrosis.

Systemic reactions: PLA2 enzymes from snake venom can induce several effects including presynaptic and/or postsynaptic neurotoxicity, myotoxicity, cardiotoxicity, initiation and/or inhibition of platelet aggregation, and hemolytic, anticoagulant, convulsant, hypotensive, and edema-inducing effects (78). PLA2 enzymes were found to stimulate the activity of cAMP-dependent kinase, Ca+2/calmodulin-dependent kinase II, and protein kinase C (PKC) (30). Subcutaneous injection of snake venom was shown to cause rapid induction of IL-6 in the serum during the first 3-6 hours, returning to normal values by 12 hours without a marked increase in serum IL-1a or TNFa (90). It was found that not only the whole venom, but also the venom myotoxic phospholipase A2 were capable of inducing a systemic release of IL-6, suggesting an indirect immune response, probably initiated by local tissue damage. It was also shown that the venom induced a rapid inversion in the ratio of neutrophils to lymphocytes. This observation suggests that the venom, besides its cytotoxic properties, can induce early hematological and immunological alterations. The involvement of IL-6 in toxicity, induced by venomous snakebites was also demonstrated. Barraviera et al. (15) demonstrated that serious hepatic damage in patients bitten by Crotalus durissus terrificus can be induced by two possible mechanisms: the venom effect on liver mitochondria and/or the cytokine effects on hepatocytes. However, there was no correlation between glomerulonephritis induced by snake venom and the elevated level of IL-6 (43).

The role of cytokines in systemic toxicity caused by bothropic venoms was also evaluated (122). Maximum levels of serum INFg in mice were detected 2 and 4 hours after injection of Bothrops asper and Bothrops jararaca venoms, respectively, while peaks of TNFa and IL-6 were attained 6 and 18 hours after injection with a positive correlation between high levels of TNFa and mortality. Both venoms caused a release of nitric oxide (NO). It was concluded that the activation of the inflammatory cascade, release of cytokines and NO play an important role in the systemic toxicity caused by bothropic venoms. Dudler et al. (42) found that PLA2 can induce antibody-independent production of IL-4 by mast cells or basophils due to the direct hydrolysis of membrane-bound phospholipids and this might trigger mast cell degranulation. Another hypothesis is that the PLA2 allergen activates mast cells by binding to a putative receptor (12,62). A high-affinity receptor for types I phospholipase A2 was identified with high affinity in various tissues. A brain receptor for different neurotoxins, which can bind to several PLA2 enzymes from various species, was also described (85,86,156).

An increase of IL-8 was documented during the first days after venomous bites, especially in the patients bitten by Crotalus snake (15). It was suggested that this chemokine might have an important role in respiratory tract disorders observed in some victims (7,8,15,107). It was also shown that cobra venom factor (CVF) can induce accumulation of neutrophils in the lung tissue by increasing IL-8 secretion and tissue permeability (82). It has recently been observed (67) that IL-8 contributes to the development of adult respiratory distress syndrome in cases of severe trauma. It is possible that the respiratory insufficiency after severe envenomation caused by Crotalus snakes is due to increased levels of IL-8 (15).

These observations suggest that the activation release of pro-inflammatory cytokines after snakebites may result in systemic reactions including shock, CNS disorders, liver, and respiratory failures.


SCORPION VENOM: Sofer et al. (146) first reported the involvement of the inflammatory systems after scorpion envenomation. These authors documented the elevation of IL-6 in the serum of 8 of 10 children severely envenomed by the scorpions L. quinquestriatus and B. judaicus. The cytokines were measured on admission to the hospital and 1 to 3 hours after the sting. IL-6 levels gradually returned to normal values at 12 and 24-hour measurements, but remained above control levels in all measurements. These results were quite similar to those found by Lomonte et al., (90) who observed an increase in IL-6 after experimental Bothrops asper envenomation. The authors concluded that the activation and release of cytokines may play an important role in the pathophysiology of envenomation after stings and may be responsible for some systemic inflammatory manifestations and organ failure. Thus, pro-inflammatory cytokines may play an important role in the pathophysiology of non-cardiogenic pulmonary edema and ARDS. This rare but serious condition was reported on several occasions (6,8). In a recent study (94), increased circulating levels of IL-1 and IL-6 in the patients with mild, moderate, and severe scorpion envenomation were reported. In a single patient of the group, who showed severe signs of envenomation, elevated IL-10 and GM-CSF were also seen; but their role in the pathogenicity of envenomation is still unclear. Another recent study showed that injection of T. serrulatus crude venom into rats induced a significant increase in lung vascular permeability due to the release of prostaglandin E2, leukotriene B4, and thromboxane A2, and a marked leukocyte infiltration of the lung. It is reasonable to suggest that these substances and cells play an important role in the genesis of venom induced lung injury (153). More human and experimental animal studies are required to determine the contribution of the inflammatory system in the genesis of scorpion envenomation.


SPIDER STINGS: Despite increasing knowledge of the pathophysiologic events following spider envenomation, the inflammatory response has scarcely been investigated. A recent study in mice (151) disclosed a similarity between toxicity of the Loxosceles intermedia venom and endotoxic shock. TNF, IL-6, IL-10, and nitric oxide were detected in the serum after venom injection, as well as in the supernatants of lymph node cultures obtained from envenomed animals, which were re-challenged by the venom in vitro. The profile of the cytokines was distinct in mouse strains differing in susceptibility to the venom. A positive correlation was found between the severity of symptoms and TNF serum levels. Since different spider venoms can cause severe local and systemic reactions including tissue cell necrosis, prostration, hypothermia, and neurological disturbances, it is suggested that the inflammatory system play a significant role in envenomation. Experimental and clinical studies are required to verify the role of the inflammatory system following spider sting, especially the black widow, which may cause severe morbidity and even mortality in man.



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Image3235.gif (888 bytes)CORRESPONDENCE TO:
S. SOFER - M.D., Pediatric Intensive Care Unit, Division of Pediatrics, Soroka Medical Center, Beer-Sheva P.O.B 151, Israel, 84101.

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