7.3 Professor R. Grimble                                                                                   Back

Cytokines and parasitic infections                   

Objective:

i) To define the importance of cytokines in parasitic infectious:

General Introduction to cytokines:

Cytokines are a range of polypeptides released from various cells of the immune system in response to a wide range of stimuli. The stimuli include invasion by bacteria, viruses and parasites, tissue trauma and physiological stress. Cytokines are produced predominantly by phagocytes, T and B lymphocytes although fibroblasts and endothelial cells are also capable of their production. The number of cytokines so far identified and characterised is increasing rapidly. The greatest amount of information has been obtained about interleukins 1 to 6 (IL1 to IL6) and tumour necrosis factors alpha and beta (TNF). All cytokines discovered to date modulate the activity of the immune system and three (IL1 & 6, and TNFA) cause widespread metabolic effects. These two main properties can be seen as a co-ordinated biological activity whereby the immune system is activated to meet the invasive challenge and in which substrate is provided to bring about tissue repair and to feed the increasingly active immune system from resources within the animal.

The cytokine cascade

Cytokines are released from producer cells as the result of interactions of various substances with receptors on the cell surface. Substances which stimulate production include components of viruses and bacteria, materials released as the result of tissue damage and cytokines themselves. Bacterial endotoxins are particularly potent inducer cytokines. The recent observations that cytokines could induce cytokine production is of great biological significance. It has been shown that TNF can induce IL1 & IL6 production, that IL1 can induce IL2 to 6 and TNF production, and that IL1 can even induce its own production. These phenomena mean that once cytokine production is initiated a further cascade of production occurs.

Metabolic effects of cytokines

Fever and loss of appetite and body weight are often observed in many diseases of viral, bacterial or parasitic origin. TNF & IL1 are mainly responsible for these effects. These cytokines and possibly IL6 are involved in many of the other metabolic effects that have been observed in disease, as summarised in figure 2.

Fever enhances the activity of the immune system and represents a substantial increase in metabolic rate- A 15Z increase in metabolic rate occurs for every 1 C rise in body temperature. The increase is purposeful as illustrated by the observation that infected Poikilotherms will try to raise body temperature by moving to warmer areas of their environment.

Interleukins 1 & 6 and TNF have major effects upon liver protein metabolism. Serum albumin synthesis is depressed and synthesis of a diverse group of protein, collectively known as acute phase proteins, is increased. Substantial quantities of zinc are removed from the blood into liver and are incorporated into metallothionein, a zinc binding protein. These metabolic changes within the liver are responsible for some of the changes in blood chemistry which are observed in many diseases, namely a fall in serum albumin and zinc and a rise in acute phase proteins.

The production of acute phase proteins is an important part of the response to infections and trauma. This fact is illustrated by the diverse functions of proteins within this group which includes fibrinogen (blood clotting), C-reactive protein and C3 complement (immuno-enhancing proteins), caeruloplasmin and metallothionein (antioxidant proteins to protect tissues from free radicals released from macrophages).

The amino acids needed for the synthesis of these proteins arise from muscle protein . Interleukin 1 and TNF brinc about los of muscle tissue and may ac-nunt for the emaciation which often arises from infections and parasitic infestations.

In addition to providing substrate for acute phase protein production,' muscle provides important materials for- nourishing the immune system. Macrophages and lymphocytes use glutamine and glucose as their preferred sources of fuel. Glutamine is produced from amino acids within muscle and glucose produced by liver from amino acids, which it receives from muscle. Thus during infections and infestations important metabolic links are forged between muscle, liver and immune system which result from the actions of cytokines.

'While cytokines have an important part to play in combating infections and infestations and in subsequent recovery, overproduction can be damaging and even life threatening. Indeed TNF has been implicated in mortalities arising from malaria. meningitis and sepsis. In addition, IL6 has also been implicated in deaths from the last two clinical conditions. It is therefore important that natural mechanisms exist to control the cascade in cytokine production, .which follows invasion or damage to the body.

Control of cytokine production.

Control is achieved in three ways. Firstly natural inhibitors to cytokine action exist. At present little is known about the nature of these inhibitors or what controls their production. The other two ways of controlling cytokine production are set in train by cytokines themselves. These are illustrated in figure 3. Cytokines bv acting on the hypothalamus lead to stimulation of the anterior pituitary and adrenal cortex. Glucocorticoids released from the latter structure inhibit cytokine production.

Glucocorticoids in turn together with cytokines such as ILI, IL6 and TNF act upon the liver to stimulate acute phase protein production. Manv of these latter molecules inhibit cytokine production. Influence of nutrition on cytokine biology.

Malnutrition and high mortality from infections and infestations often go hand in hand. Indeed gross impairment of immune function occurs in malnourished populations. An increasing body of evidence shows that cytokine production is reduced by malnutrition. Studies in well nourished subjects show that dietary fat can influence cytokine production. In particular fish oil can reduce the ability of macrophages to produce IL1, IL6 and TNF. This latter observation could explain why fish oil is able to reduce inflammatory symptoms in conditions such as rheumatoid arthritis and inflammatory bowel disease.

References:

R.F. Grimble   Interaction between nutrients, pro-inflammatory cytokines   and inflammation. Clinical Science 1996; 91: 121-130.


R.F. Grimble Dietary lipids and the inflammatory response.  Proceedings of the Nutrition Society 1998; 57: 1-8.

Copies of these papers and related papers are available in  the BS360 boxes in the restricted loan section of the
library.

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Dr. R. Grimble 2006