Does Interleukin Play A Role In Vascular Disease Biology Essay

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The main function of arteries is to transport blood and oxygen to the tissues in the body, and any obstruction can lead to reduced function, tissue damage and eventually death of the tissue (Worthley S, 2001). Vascular diseases are categorized according to the location they are mainly found in and also on the symptoms they show. The types of vascular diseases are -

This type of vascular disease takes place when the arteries near the heart are blocked due to excessive presence of lipids in the arteries. It is also known as atherosclerosis, which will be discussed in more details later in the essay. The symptoms of cardiovascular disease are severe chest pain, breathlessness, etc. When the normal blood flow in the artery is completely or partially blocked, it leads to a heart attack or a myocardial infarction. There are various factors which leads to atherosclerosis namely, use of excessive oil (fats) in the diet (high intake of cholesterol), smoking, obesity, etc. The general pathophysiology of the disease will be discussed later (Worthley S, 2001).

This type of vascular disease takes place when the arteries inside the brain are narrowed and rupture and later lead to cerebral thrombosis. There are high chances of the arteries rupturing and giving rise to cerebral haemorrhage. The symptoms of cerebrovascular disease are difficulty in swallowing, problems with balance and coordination. The more lethal symptoms are paralysis, or stroke leading to sudden death. Factors contributing to cerebrovascular disease are smoking, hypertension, use of alcohol, injury to the brain, etc. Certain medications are available like taking drugs or surgery.

Peripheral Vascular disease -

This type of vascular disease takes place when the arteries in the legs are blocked. This is not much of a serious type as the pain can be relieved by resting. But, in cases with more advanced blockage, this can lead to ulceration of the lower leg as well as gangrene in the toes and feet. The shortage of supply of blood to the legs for all types of physical work leads to the pain in the legs. Factors like obesity, diabetes and no daily exercise contribute a lot in peripheral vascular disease. Treatments available include taking medicines or undergoing a surgery.

Atherosclerosis -

Atherosclerosis is considered as one of the world's most lethal disease. It is responsible for at least 50% death in Western countries. Mostly, the deaths are caused by heart attack taking place due to the rupture of the atherosclerotic plaque and thrombosis (Greenow K et al, 2005). Thus, it has become extremely important to find various medications and device preventive measures. For this sole purpose, researchers are currently considering various approaches.

Role of ApoE in atherosclerosis -

ApoE is Apolipoprotein E, which is a multifunctional protein present on the surface of lipoprotein and is essential for the regulation of atherosclerosis. The understanding of role of ApoE in atherosclerosis is important as almost all mouse models designed are based on either presence or absence of ApoE protein.

Monocytes and Macrophages can only express ApoE; it is believed to be found in abundance in atherosclerotic plaques. In vivo studies reveal that Macrophages present inside the plaque synthesize ApoE, independent of the severity of the plaque (Rosenfeld M et al, 1993). ApoE protein has many functions such as regulation of inflammatory responses, inhibition of oxidation of LDL (Low Density Lipoproteins), uptake of lipoprotein particles, etc (Greenow K et al, 2005).

It has been proved that ApoE deficient (ApoE -/-) mice show high level of atherosclerotic plaques as compared to the wild type when same diet is given to both the mice. The role of ApoE in humans is much more complex than in mice (Davignon J et al, 1999). But, mouse models are considered as one of the best ways to study a disease.

Pathophysiology of atherosclerosis -

Atherosclerosis is said to be an inflammatory disease which arises due to the normal immune response to an injury in a lipid environment. The major factor causing atherosclerosis is high intake of cholesterol in the diet which leads to presence of more LDL (Low Density Lipoprotein) in the blood stream. This LDL gets into the innermost layer (Intima) of the artery and then gets converted into ox-LDL (oxidized-LDL) with the help of oxygen radicals and certain enzymes. Monocytes and T - cells are also present due to the immune response generated. They produce pro-inflammatory cytokines which helps in the activation of the endothelial cells of the artery. The ox-LDL molecules in turn also increases the permeability of the endothelial cells by activating VCAM - 1 (Vascular Cell Adhesion Molecule - 1) present on the surface of endothelial cells. Due to this activation, more Monocytes enter the intima (with the help of certain chemoattractant gradients) and more immune response is generated. Later, due to the presence of M-CSF (Macrophage Colony Stimulating Factor), the Monocytes are differentiated into macrophages. These newly formed Macrophages contain scavenger receptors which bind to the ox-LDL present in the intima and thus they get embedded into the macrophages, giving rise to foam cells. New entering T cells bind with the Macrophages present inside the intima with the help CD40L- CD40 ligand. This binding releases more pro-inflammatory cytokines and the balance between pro-inflammatory and anti-inflammatory cytokines changes. There are many changes which take place due to the release of cytokines like increase in cell adhesion molecules, increase in permeability of endothelial cells, decrease in collagen production, etc. The Smooth Muscle Cells (SMCs) covers the foam cells and forms the necrotic core of the lesion. The foam cells undergo apoptosis inside the necrotic core. A fibrous cap made up of collagen covers the SMCs and thereby protecting it. There is regular wear and tear of the endothelial cells due to the normal blood flow and hence, the fibrous cap ruptures and the plaque is released in the blood flow. Thrombosis takes place and it leads to blockage of the artery. Depending on the location of the block, it can lead to myocardial infarction or stroke (Hansson G and Libby P, 2006).

Migration of LDL into the intima of the artery from the blood stream

Conversion of LDL into ox-LDL due to the presence of certain oxygen radicals and enzymes

Activation of VCAM - 1 takes place and thus increasing the permeability of the endothelial cells to Monocytes and T - cells.

Entry of Monocytes and T - cells increases into the intima. Monocytes are converted into Macrophages due to the presence of M-CSF.

The Macrophages consists of Scavenger receptors on the membrane and thus binds and engulfs ox-LDL from the intima.

This gives rise to the formation of foam cells.

The entering T cells bind with Macrophages with the help of CD40 - CD40L ligand and thus increasing the inflammatory response.

The Foam cells undergo apoptosis after they are covered with SMCs and form a necrotic core.

A fibrous cap covers the plaque protecting it. Injury to the endothelial cells leads to rupturing of the fibrous cap and release of the plaque in the blood stream.

Thrombosis takes place and thus leads to blockage of the artery.

Depending on the location of the blockage, myocardial infarction can take place.

There are various factors which contribute in the progression of atherosclerosis, but most important are cytokines. There are two types of cytokines present namely, pro-inflammatory cytokines and anti-inflammatory cytokines.

Pro-inflammatory cytokines -

TNF - α -

TNF - α is one of the most important pro-inflammatory cytokine which carry out functions like cytokine expression, increases endothelial permeability as well as stimulates VCAM -1 molecules.

IL - 1 -

Interleukin 1 is mainly of two types IL - 1α and IL - 1β which carry out functions like co-stimulation of endothelial cells, SMCs activation which leads to excess migration and proliferation and increasing the inflammation.

IL - 2 -

Interleukin 2 mainly helps in activation of Endothelial Cells (ECs) by stimulating VCAM -1 adhesion molecule and also in proliferation of SMCs.

There are many more pro-inflammatory cytokines which contribute to the overall progression of the disease like IL-6, IFN-γ, etc.

Anti-Inflammatory cytokines -

IL - 10 -

Interleukin 10 is one of the most important anti-inflammatory cytokine which mainly inhibits pro-inflammatory cytokine production and also inhibits Th1 responses.

IL - 9 -

Interleukin 9 mainly functions by inhibiting Monocytes activation and it also stimulates TGF - β in Monocytes. It also contains anti - atherogenic properties.

TGF - β -

TGF - β is an important anti-inflammatory cytokine whose main functions are providing stability to the plaque and also to regulate SMC matrix formation. It also consists of anti - atherogenic properties.

There are other anti-inflammatory cytokines who try to block the action of pro-inflammatory cytokines during the progression of the disease like IL-4, IL-13, etc (Sprague A and Khalil R, 2009).

Cytokine expression

Increase permeability of ECs

Fig - Some of the functions of Pro - and Anti - Inflammatory cytokines.

Activation of VCAM - 1

Pro-inflammatory Cytokines like IL -1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Anti-inflammatory Cytokines like IL -10, TGF - β, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Pro-inflammatory Cytokines like IL - 1, TNF - α, etc

Inhibition of Th1 responses

Anti - Atherogenic properties

Inhibition of pro - inflammatory cytokine production

In 1913, Anitschkov NN proved that atherosclerosis is caused only due to the high cholesterol level in the blood. He stated that it is only the lipids which accumulate inside the intima of the artery and later on rupture to form blockage. But it was in 1960, Anitschkov and Virchow, separately found out that there were many immunological cells involved in the progression of atherosclerosis. This was studied and later understood that although lipids play a very essential role in the disease, it is not the only factor. Further studies on the disease and also by understanding the mouse models, it was proved that atherosclerosis is caused due to a normal immune response in presence of lipids. Thus, after these findings when atherosclerosis was confirmed to be an inflammatory disease, many possible ways for treating it were studied (Hansson G, 2009).

Normal immune response -

The difference between the normal immune response and the immune response involved in vascular disease helps us to understand the topic clearly. In normal immune response, when a pathogen enters into the blood stream, the macrophages engulf the pathogen and present its antigen fragment on its surface (Thus, becoming an Antigen Presenting Cell). Later, T-helper cell recognises the antigen and binds to it. When the macrophage and T - helper cell bind, the macrophage releases IL - 1 which in turn makes T - helper cell release IL - 2. This IL - 2 activates cytotoxic T cells which later produces millions of copies and bind to the infected cell and destroys it. IL - 2 also activates B cells which produce antibodies complementary to the antigen. T - Helper cells are required to activate B cells which make them divide and produce millions of antibodies. These antibodies flow in the blood stream and bind to the antigen present on the pathogens and thus they are destroyed by macrophages. This is the entire process of immune response to infection.

If we compare this response to the response involved in vascular disease, we can figure out that macrophages are involved in both the processes. The only difference is that, when Macrophage enters inside the intima of an artery, it engulfs ox-LDL (thinking that as a pathogen) and forms foam cells. Foam cells release high levels of IL - 1 leading to the activation of endothelial cells and thus, more immune response is generated.

Interleukin - 1 -

Interleukin - 1 (IL-1) is an important pro-inflammatory cytokine which plays a big role in the progression of atherosclerosis. It is responsible for variety of functions like stimulation of VCAM - 1 adhesion molecules, increasing the permeability of the endothelial cells, increasing cytokine expression in the intima, etc. IL - 1 is subdivided into 2 agonistic molecules IL - 1α and IL - 1β and one antagonist molecule IL - 1Ra (IL - 1 receptor antagonist). Both IL - 1α and IL - 1β are required in atherosclerosis. IL - 1Ra act as an inhibitor of atherosclerosis and is considered as a possible therapeutic target. IL - 1Ra inhibits the binding of IL - 1α or IL - 1β to the IL - 1 receptor type 1 and IL - 1 receptor type 2. Thus, IL - 1Ra regulates the binding of IL - 1α and IL - 1β and thereby regulates its functioning (Kamari Y et al, 2007).

Despite feeding the mice with high cholesterol diet, Kamari et al, found that the IL - 1α deficient mouse did not shown atherogenesis. However, it was also proved that reduction in IL - 1β in mice by using knock out technique lead to a reduced level of atherosclerotic plaque formation (Kirii H et al, 2003). Although, the only difference was Kirii et al used ApoE - deficient mice with IL - 1β knockout. This proves that IL - 1α and IL - 1β is indeed important in atherosclerosis.

There are certain experiments carried out in order to confirm the fact that IL - 1 is one of the essential factors necessary. Some of them are listed below -

In 1991, it was found out that IL - 1 was expressed by a variety of immunologically important cells, but most prominently by foam cells (macrophages containing LDL) during atherosclerosis. This was studied using sections of iliac arteries obtained from monkeys and later identifying the different types of cells obtained (Moyer C et al, 1991).

As it was known that IL - 1Ra counter regulates the action of IL - 1α and IL - 1β, an experiment in 2003 proved that lack of IL - 1Ra actually leads to quicker neointima formation. IL - 1β is considered as a chemoattractant for SMCs which helps migration take place. This paper stated that neointima formation takes place due to stimulation of SMCs and migration of Monocytes into the intima. They noticed that plaque formation takes place more rapidly in IL - 1Ra deficient mice as compared to the normal wild type (WT) mice (Isoda K et al, 2003).

Using transgenic mouse model with ApoE deficiency, Soussi F et al, proved that IL - 1 plays a very important role in atherosclerosis. The main aim of this experiment was to show the balance between IL - 1 and IL - 1Ra in atherosclerosis. They proved that, IL - 1Ra when present inhibits atherosclerosis even when the mice are fed on high cholesterol diet (Soussi F et al, 2005). One experiment also states that in atherosclerotic plaques, IL - 1β is found more than IL - 1Ra as compared to normal artery. The ratio of IL - 1β to IL - 1Ra is more towards the pro - inflammatory side in atherosclerosis (Olofsson P et al, 2009).

In 2000, Rectenwald J et al said that IL - 1 receptor played an important role. They proved that mice deficient in IL - 1 receptor did not show atherogenesis as compared to the other. It was because these deficient mice do not up regulate VCAM - 1 molecule, thereby inhibiting the activation of the endothelial cells (Rectenwald J et al, 2000). They showed the importance of IL - 1 signalling in atherosclerosis. Later, it was proved using mouse models that IL - 1β is more involved in the progression of the disease as compared to IL - 1α. This was also due to the fact that the signalling of IL - 1β takes place through IL - 1 receptor type 1. This experiment clearly stated that, deficiency of IL - 1β in mice did not lead to atherogenesis. They also mentioned that maybe IL - 1β should be considered as a therapeutic target (Chamberlain J et al, 2006).

As it is clear that IL - 1 receptor type 1 is necessary for transmitting signals from both IL - 1, presence of IL -1Ra inhibits the binding of IL - 1 to the receptor and thereby making it functionless. This latest experiment carried out in 2009, states that IL - 1 inhibition reduces the atheroma formation in ApoE deficient mice, even though they are fed on cholesterol rich diet. IL - 1 inhibition is carried out by knocking out IL - 1 receptor gene. This proves that, presence or absence of IL - 1 plays a major role (Chamberlain J et al, 2009).

Therapies available -

There are many risk factors which led to the increase in the chances of an individual having a heart stroke due to atherosclerosis. Consuming high cholesterol containing diet is one of the most basic factors as it leads to higher accumulation of LDL in the blood stream. Lack of exercise and obesity are also equally contributing. Other factors like hypertension, smoking, etc also play a part in some of the cases (Worthley S et al, 2001).

Statins are currently used to treat patients suffering from atherosclerosis as it inhibits the 3-hydroxy-3-methylglutaryl Coenzyme A reductase (HMG CoA) enzyme which is responsible for cholesterol biosynthesis. When certain statins like fluvastatin, simvastatin, etc were studied on ApoE deficient mice, it did not show much effect. Although some contrary reports suggested that these statins showed a reduction in lipid deposition in ApoE deficient mice. It was understood that statins show much better cholesterol reducing effect in human than in mouse models (Zadelaar S et al, 2007).

Another latest drug, Ezetimibe showed great results in mouse models reducing atherosclerosis by 97% in ApoE deficient mice. This drug can be used alone or in conjugation with statins. The mode of action of Ezetimibe is to inhibit the uptake and absorption of cholesterol in the intestines. On the other hand, Avasimibe is an inhibitor of Acyl CoA: cholesterol acyltransferase - 1 (ACAT - 1), which removes free cholesterol from the foam cells and thus stabilizes the plaque. It has shown good results in E3L mouse model (Zadelaar S et al, 2007).

Therapeutic targets considering only the role of IL - 1 majorly involves IL - 1Ra and its signalling. Interfering with IL - 1 signalling in vascular wall, up regulation of IL - 1ra activity or down regulation of IL - 1 production in vascular wall are some of the possible avenues where research is been carried out.

In 1998, it was proved that IL - 1 activity plays a very important role in the early stages of atherosclerosis. It was predicted in this paper, that down regulation of the activity of IL - 1 can act as a therapeutic target. Here, they have mentioned that presence of IL - 1 constitutes the fatty streak formation in the initial stages. They studied the effect of IL - 1 on ApoE deficient mice and found out that blocking IL - 1 activity can stabilize the plaque (Elhage R et al, 1998).

When Morton et al, studied the important of IL - 1ra in porcine model, they found out that presence of IL - 1ra reduced neointima formation after injury. They discovered that when IL - 1ra therapy was continuously given for 14days, it lead to a 23% decrease in the neointima region. Thereby, stating that up regulation of IL - 1ra activity can be considered to have a therapeutic application (Morton A et al, 2005).

In 2009, an experiment carried out by Chamberlain et al, proved that inhibition of IL - 1 reduces atheroma formation. They inhibited IL - 1 by knocking out the genes responsible for IL - 1 receptor as well as ApoE in mice. These results lead to the fact that inhibition of IL - 1 signalling will make a difference in human (Chamberlain J et al, 2009).

Although, it has been proved long time back that IL - 1 does play an important role in atherosclerosis, it was found lately that IL - 1β is more involved in the progression of the disease than IL - 1α. It is also clear that presence of IL - 1ra has shown good results in the reduction of atherosclerosis at least in the mouse models. There are various treatments currently used, but medications considering IL - 1 are also been found out. It is seen that IL - 1 is not the only factor associated in the pathophysiology of the disease so inhibiting the activity of other factors can also be considered as therapeutic targets. However, atherosclerosis can be prevented to some extent by balanced diet and regular exercise, it is also important to discover all possible treatments of this disease. Hence, considering the role of IL - 1, various avenues have opened up for more research to take place in this field.