p.p1 mediators involved in many processes throughout the body.

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Cytokines are small protein mediators involved in many processes throughout the body. They play a key role in cell growth and differentiation, immunity, inflammation and healing and repair. Cytokines can be produced by a wide variety of cell types including lymphocytes, monocytes, macrophages, endothelial cells and fibroblasts (1). Cytokines are generally involved in events that occur locally. Although cytokines and hormones act similarly in many ways, where they act in the body is a distinction between the two. Hormones are transported via the bloodstream to target areas throughout the body (1). Cytokines physiologic effects are exerted locally into tissues via paracrine or autocrine type mechanisms. This means that cytokines either act on the same cells that produced them, or on cells nearby. However, some cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-?) can have systemic effects, which will be discussed later on. In general, cytokines bind with very high affinity to cell surface receptors. Cytokine receptor presence is generally low, however the high binding affinity combats this. Cytokine receptors can also upregulate upon activation to a varying degree (2). In normal healthy tissue, cytokine expression is low, however this production increases drastically during events that cause tissue stress or trauma (3). During times of stress in the body, the activation of the Hypothalamic-Pituitary-Adrenal (HPA) axis also has functional importance. One reason for this is that adrenal glucocorticoids (GC) have been shown to have a significant role in regulating immunologic processes. Cytokines have been implicated in the activation of the HPA axis. Most notably IL-1, IL-6 and TNF-? have been identified as key players.  IL-1, IL-6 and TNF-? have several shared neuroendocrine actions such as activation of the HPA axis, suppression of the Hypothalamic-Pituitary-Gonadal (HPG) axis and suppression of the Hypothalamic-Pituitary-Thyroid (HPT) axis (3). This immune-neuroendocrine regulatory feedback mechanism becomes vital during high levels of stress in the body. This paper aims to examine the pathways and processes that mediate the production and actions of cytokines in the body during periods of exposure to severe infection.
All living organisms develop a system to protect themselves from foreign and exogenous pathogens that present a threat. As mentioned before, cytokines are involved in many different processes throughout the body, one of which being cell growth and differentiation. Cytokines play a critical role in the differentiation and proliferation of T lymphocytes, so they are closely related to the development of immunity against various infectious agents such as bacteria and viruses (1). Bacterial and viral infections have many things in common, including their cause (microbes) and the way in which they can be spread from person to person. There are also common cytokines implicated in both types of infections. These cytokines include IL-1, IL-6, and TNF-?. However, the concentrations of these cytokines vary depending on the type of infection. Individuals infected with a bacterial infection for example, bacterial pneumonia, had significantly higher blood sera levels of  IL-1, IL-6, and TNF-? when compared to individuals with a viral infection (tick borne encephalitis) (4). Bacterial and viral infections also share a common transcription factor that is activated in both types of infection. NF-?B is known to be the hallmark transcription factor and is implicated in most types of infections (5). Next we will take a closer look at the effects of cytokine production in specific examples of both types of infections. 
 Cytokines can be a driving force behind the pathogenic activity of some bacterial infections, and can represent an important defense mechanisms in others. One type of bacterial infection that cytokine activity has widely been examined in is sepsis. Sepsis is a result of an infection that can cause drastic changes in the body which can be life threatening. This infection is thought to occur on three different levels. The lowest level is referred to as sepsis, which is when the infection enters the bloodstream and begins to cause inflammation throughout the body. A level above that is referred to as severe sepsis, which occurs when the infection becomes so damaging, that it begins to affect the ability of organs to function properly. Lastly, septic shock is when the body experiences a large drop in blood pressure that can lead to multiorgan failure, respiratory failure, stroke or even death (6). Gram negative bacteria are the most common cause of sepsis. Endotoxins contained in these gram negative bacteria were shown to initiate the cascade of disturbances that disrupts the homeostasis of regular cytokine production in the body. The main cytokine indicated in the progression of septic shock is TNF-?. However, IL1, IL-6 and IFN-? seem to play a major role as well (7). TNF-? when injected into experimental animals was shown to induce pathophysiological changes similar to those observed by endotoxin. Bacterial infection was also shown to cause an increased production of TNF-? in vivo and in vitro. Additionally, TNF-? plasma concentrations drastically rose when experimental animals were injected with sublethal doses of endotoxin (7). TNF-? spike is the first cytokine rise that was observed following endotoxin injection into experimental animals. An IL-1 rise was observed shortly after, followed by a rise in IL-6 concentrations. High IFN-? levels have also been indicated in severe sepsis and IFN-? has been shown to potentiate TNF-? activity when the agents are given simultaneously. Antibodies against these cytokines have been show to limit the detrimental effect endotoxin exposure can have. When antibodies against TNF-? were given prior to endotoxin exposure. a reduced development of septic shock was observed. Anti-TNF-? antibodies also reduced the levels of IL-1 and IL-6 produced (7). 
The body can be exposed to a variety of different viral pathogens that can cause cytokine production. Viral surface glycoproteins, double-stranded RNA, and intracellular viral proteins represent a few of these different types of pathogens (8). Human Immunodeficiency Virus (HIV) can cause progressive degeneration of the immune system by targeting cells that express the CD4 molecule. Primarily T lymphocytes, monocytes and macrophages through recognition of the CD4 receptor. As a result, CD4 T lymphocyte numbers are decreased, T cells and macrophages function defectively, and cytokine production is dysregulated (9). These particular cell types express chemokine coreceptors that allow for HIV-1 entry and cellular tropism ability. Eventually the immune system becomes unable to keep up with the expansive turnover and death of cells, leaving the body in a state of immune imbalance. Several studies have shown that HIV-1 is associated with a switch from a T-helper type 1 to T-helper type 2 response. This means that the body begins to produce lower levels of  IL-2 and IFN-? and begins to produce higher levels of proinflammatory cytokines like IL-1, IL-6, TNF-? (9). The pathophysiology of HIV-1 highlights the complex role cytokine activity can play in viral infections. Cytokines can be both stimulatory and inhibitory. Infection of monocyte derived macrophages (MDM) with HIV-1 resulted in the upregulation and continuous secretion of IL-1 in culture.  Monocytes obtained from HIV-infected individuals also displayed production of biologically active IL-1? and IL-1? proteins. When observing IL-6, infection of MDM with HIV-1 also resulted in upregulation of IL-6 in culture (9). They also observed that IL-6 secretion is increased in sera of HIV infected individuals. Infection of CD4 T cells with HIV-1 enhanced their secretion of TNF-?. Conversely, exposure of T cells to anti-TNF-? antibodies, decreases HIV-1 production and prevented HIV-induced CD4 T cell depletion. Increased levels of TNF-? were also found in the sera of HIV-infected individuals. The increased production of these proinflammatory cytokines helps to keep HIV-1 active and able to replicate in the body.  As mentioned before, cytokines can aid in the progression or regression of certain infections (9). Studies have shown that the abnormal cytokine profile observed in HIV-1 can partially be reversed via the administration of active antiretroviral therapies. By increasing IL-2 and IFN-? secretion, HIV-1 replication was suppressed and CD4 T cell counts were partially restored (9). Cytokine and antiretroviral therapies could be a promising treatment option for viral infections moving forward.
During severe infection, cytokines interact with the adrenal and reproductive axes through a variety of different way. A bidirectional relationship exists between the immune and neuroendocrine systems. An imbalance in this relationship may contribute to a number of pathologies especially those that are stress related. When the body is exposed to stress related signals, the adrenal medulla responds in various ways. The adrenal medulla contains chromaffin cells which have been implicated in biologic responses to stress (10). These chromaffin cells respond to stress signals by releasing catecholamines such as adrenaline and noradrenaline, and active neuropeptides. Cytokines secreted by activated immune cells during severe infection can influence the activity of adrenal medullary output. Contrariwise, components secreted from the adrenal medulla can affect immune cell function. IL-6 is one cytokine that has been indicated in the adrenal axes during infection. IL-1 and TNF-? levels rise when the body is exposed to pathogens (10). The rise of these cytokines causes a rise in the level of IL-6 which is referred to as the “bottom up regulation of IL-6. Conversely,  the ‘top-down’ regulation of IL-6 occurs when the HPA-axis is activated after a stressful event and cortisol, adrenaline and noradrenaline are released which enhance IL-6 secretion levels in non inflamed tissue. IL-6 and its receptors have also been observed in adrenal glands of several species indicating a paracrine or autocrine role within the tissue (10). Within the adrenal cortex, IL-6 has been shown to directly stimulate increased steroid release. Another cytokine involved with the adrenal axes is IL-1. Proinflammatory IL-1 cytokines can be generated by tissues other than activated immune cells such as neuroendocrine tissue. IL-1 has been observed in the cortex and medulla of the rat adrenal gland. Multiple studies have shown that adrenal medullary chromaffin cells can both secrete IL-1 and respond to the cytokine (10). This once again indicates that IL-1 might have paracrine or autocrine effects within the gland just like IL-6. During stress IL-1 has also been indicated in modulating synthesis and release of catecholamines and neuropeptides from the adrenal medulla chromaffin cells. Lastly, TNF-? is also involved in adrenal axes interaction during infection. TNF-? expression has been observed in adrenal gland tissue. Similarly to IL-1, TNF-? is also involved in modulating the production and release of neuropeptides and catecholamines from chromaffin cells (10).  All of these interaction highlight the bi-directional relationship that exists between the immune and neuroendocrine systems. The adrenal medulla has a critically important role in maintaining basal and stress-induced catecholamine secretion. This systems seems to be regulated by the influence of cytokines. Conversely, cytokine secretion seems to be influenced by signals sent from the adrenal axes. The homeostasis of these systems aids the body in its ability to fight off and protect itself from severe infection.   
During periods of severe infection, reproductive function is drastically impaired. Cytokines are thought to be involved in this process (11). Lipopolysaccharide (LPS) is a glycolipid of gram negative bacteria that is used to mimic the effects of sepsis. LPS disrupts reproductive capability in hosts by compromising the function of several agents including proinflammatory cytokines (12). When LPS was distributed in experimental rats, IL-1 and TNF-? were shown to suppress the release of LH by blocking GnRH secretion leading to the impairment of the reproductive axes. IL-6 effects of this systems have been contested, but for the most part it is not thought to be involved (12). This suppression of the reproductive axes during severe infection could be potentially advantageous to the host. Less energy in the body would be used to support this system, which could prove to be beneficial when the body has the difficult task of fighting off severe infections. 
As we have learned from our examination of cytokine function in different types of infection, they can either have protective or damaging effects. On one hand, cytokines are central to the development of effective immunity against a variety of pathogens and have been shown countlessly to control and suppress the pathophysiology of a variety of different infections. However, cytokines have also been observed to perpetuate the detrimental effects of infections via their upregulation and microbial growth. It appears that some microbes have developed strategies over time that allow them to evade the onslaught of cytokines. which attest to their ability to develop resistance. However some microbes have evolved to develop cytokine receptors that allow them to use cytokines as growth factors to support their multiplication. These microbes appear to have succeeded in acquiring host DNA and using that to express appropriate receptors on their surfaces. Cytokine receptors could then act as virulence factors in the progressions of particular pathogens. Acknowledging this distinction is important when looking to use cytokines as potential options for therapies. Imbalances created as a result of cytokine therapy have the potential to lead to immunoregulatory disruptions which could manifest as immune disorders, autoimmune diseases, or other pathological effects (13).
Not much is known on the mechanism by which cytokines can regulate antimicrobial activities. As we know, bacteria sepsis is indicated by a rise in TNF-? IL-1, and IL-6 levels. One potential manipulation would be to limit the synthesis and expression of these cytokines during shock. Limiting the expression of TNF-? and IL-1 was shown to reduce the the severity of the body’s response to bacterial microbes (14). In one study, cyclooxygenase and histamine type 2 receptors were observed to increase endotoxin-induced synthesis of TNF-? and IL-1. By administering cyclooxygenase inhibitors and histamine type 2 receptor antagonist, the transcription of these cytokines was suppressed. IL-4 was also shown the suppress the transcription of these cytokines (14). Studies with corticosteroids have also been done. They were shown to slow down the transcription and synthesis of IL-1 when they were administered before the endotoxin induced transcription of IL-1 was initiated. Therefore, corticosteroids would have little effect on inhibiting the synthesis of detrimental cytokines once their genes have already been expressed (14). However, continued studies on these agent could still be useful. Another potential manipulation of cytokines as a therapy option would be to administer antagonist antibodies to TNF-?. We know this is the main cytokine indicated in the progression of bacterial sepsis. Anti-TNF-? antibodies were shown to protect experimental animals from death due to sepsis. When these experimental animals were exposed to anti-TNF-? antibodies, a decrease in IL-1 and IL-6 levels were also observed indicated that TNF-? has some control on levels of their production (14). Further studies examining the effects of anti-IL-1 and anti-IL-6 antibodies could also be tested to see if they would have any protective effects. Another potential therapy manipulation would be to examine the use of naturally occurring inhibitors to the cytokines that play a role in the progression of sepsis. For example, lipoproteins are a naturally occurring structure that has been shown to limit IL-1 and IL-6 activity. Scientist have been able to identify a naturally occurring IL-1 inhibitor known as IL-1ra. IL-1ra inhibited the binding activity of IL-1 and was shown to prevent death in experimental rat exposed to endotoxin shock. It was also shown to blocks the production of IL-1-induced IL-1, TNF-? , and IL-6 (14). Lastly, scientist observed the effects of soluble cytokine receptors. TNF-? and IL-6 have naturally occurring soluble receptors. These soluble receptors can be found naturally in urine. Soluble receptors are shed from the receptors contained on cell surface as extracellular segments. Naturally occurring IL-1 soluble receptors have not been observed however, recombinant soluble IL-1 type II receptors (IL-1RtI) have been constructed. When soluble IL-1RtI was administered to rats exposed to bacterial sepsis, the survival rate increased. Soluble TNF-? receptors obtained from human urine were shown to bind to TNF-? with the same affinity of TNF-? receptors found on cell surfaces. The soluble TNF-? receptors also inhibited the pathogenic activity of TNF-? (14). These are a few of the therapeutic manipulations of cytokines being employed. As a better understanding of the biological effects of cytokines during infections becomes more understood, alternative modes of treatment will emerge.
Cytokines play a complex role in the human body when it is exposed to different types of infections and pathogens. They stimulate the release of a large number of factors which can interact with a series of diverse and complex networks. Cytokines unique characteristics give them very different functions in varying pathophysiologies. The biological effects of cytokines are determined by unique factors within the environments of their site of action. Cytokines have both protective and damaging effects in different disease states and have complex relationships with different regulated systems throughout the body. Moving forward, as cytokine function becomes better understood, manipulations of them as treatment options for a variety of infections looks promising. 

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