Elsevier

Nutrition

Volume 14, Issues 7–8, July–August 1998, Pages 634-640
Nutrition

Original Articles
Nutritional modulation of cytokine biology

https://doi.org/10.1016/S0899-9007(98)00010-0Get rights and content

Abstract

The pro-inflammatory cytokines and oxidant molecules produced during the inflammatory response, which follows infection and injury, may be beneficial, or detrimental to the patient, depending on the amounts and contexts in which they are produced. Aberrant or excessive production has been implicated in inflammatory disease, and sepsis. The upregulation of cytokine production by NFκB and NFIL-6 activation by oxidants increases the likelihood of cytokine-induced mortality and morbidity. Complex systems exist for the control of cytokine production and oxidant actions. The former include the hormones of the hypothalamo-pituitary-adrenal axis, acute phase proteins, and endogenous inhibitors of interleukin (IL)-1 and tumor necrosis factor (TNF). The latter include endogenously synthesized antioxidants, such as glutathione and dietary antioxidants, such as tocopherols, ascorbates and cachectins. Nutrients change cytokine production and potency by influencing tissue concentrations of many of the molecules involved in cytokine biology. Monounsaturated fatty acids and ω-3 polyunsaturated fatty acids (PUFAs) suppress TNF and IL-1 production and actions, while n-6 PUFAs exert the opposite effect. Changes in eicosanoid production are more likely to underlie this effect than alterations in membrane fluidity. Low antioxidant intake results in enhanced cytokine production and effects. The anorexia that follows infection and injury, may be purposeful to permit release of substrate from endogenous sources to support and control the inflammatory process. Therefore, prior as well as concurrent nutrient intake are of importance in determining the outcome of the inflammatory response.

Introduction

Infection and injury activate the immune system and bring about widespread metabolic changes. Both phenomena are closely interrelated and form part of a complex and coordinated response, which disadvantages and destroys the invading organism, facilitates repair of damaged tissue and restores tissue function to normal.

A complex variety of soluble mediators are released from cells of the immune system and hepatocytes.1, 2, 3 The mediators include immunoglobulins, complement proteins, platelet-activating factor, and cytokines. Cytokines are a large group of peptides and proteins that are involved in signaling between the cells of the immune system and in modifying metabolism. Cytokines include interleukins (IL), interferons, colony stimulating factors, tumor necrosis factors (TNF), and transforming growth factors (TGF). A grouping of three cytokines, IL-1, IL-6, and TNF-α not only mediate and modulate an enhanced level of activity in the immune system but bring about widespread metabolic changes. These molecules are usually described as pro-inflammatory cytokines as they are key mediators of inflammation. A number of cell types produce IL-1, IL-6, and TNF-α. These include phagocytic leucocytes, T and B lymphocytes, mast cells, fibroblasts and endothelial cells.4, 5, 6 Once induced, IL-1 and TNF can stimulate production of each other and of IL-6. Therefore, a cascade of pro-inflammatory cytokines occurs following the initial inflammatory stimulus.7 Other events occur that indirectly upregulate proinflammatory cytokine production. IL-1 and TNF are potent stimulants of oxidant molecule production. In particular, nitric oxide, hydrogen peroxide, and superoxide radicals are produced by phagocytes.8 These oxidants enhance cytokine production.

The production of cytokines and oxidant molecules is part of highly effective mechanism for creating a hostile environment for pathogens within the body.9

The essential nature of cytokines in recovery from infection and trauma is indicated by the poor prognosis of malnourished patients who have a reduced ability for cytokine production.10, 11 Poor wound healing in such patients may be due to the fact that TNF-α is an important inducer of TGF that play a crucial part in the process.

This review describes the metabolic effects of IL-1, IL-6, and TNF-α, the innate systems for protecting the subject from the potentially pathological effects of enhanced cytokine production and the modulatory role which nutrients exert on cytokine biology.

Section snippets

Cytokines and the metabolic consequences of infection and injury

Fever, loss of appetite, and wasting of peripheral tissues are salient features of infected and injured individuals. The wasting results in loss of tissue lipid, protein, and micronutrients. Widespread metabolic changes underlie the wasting process. They facilitate the delivery of nutrients such as glutamine, amino acids, glucose, fatty acids, and micronutrients to the immune system, assist repair of tissues, control cytokine production, protect healthy tissue from the effects of free radicals

Potential for damage to the host from the inflammatory response

Paradoxically, although cytokines play an important role in the response to infection and injury, they can exert damaging and lethal effects on the host. The molecules are highly potent and several biological events enhance cytokine production increasing the potential for damage to the host. In addition, there may be genetic features that predispose subjects to high levels of cytokine production. Oxidant molecules upregulate cytokine production by activation of nuclear transcription factors

Modulation of cytokine biology by nutrients

The metabolic aspects of inflammation, previously described, are mediated by a range of secondary messengers and cell signaling mechanisms, which offer broad scope for nutritional modulation. Nutritional support, in the form of lipids and antioxidants, may act at these foci and amino acid provision may alter the availability of substrate for the production of proteins and peptides important in the inflammatory process.

Cytokines may have beneficial or detrimental effects, depending on the

Modulation of cytokine production and biological effects by fats

Fats may exert modulatory effects by influencing the ability of cells to produce cytokines and the ability of target tissues to respond to cytokines. This topic has been reviewed in detail elsewhere.54, 55 The fatty acids in dietary fat consist of three main types according to chemical composition. These are saturated fatty acids such as stearic and palmitic acid, which are found in highest concentrations in saturated fats such as beef fat, coconut oil, and butter; ω-9 monounsaturated fatty

Modulation of cytokine biology by oxidants and antioxidant status

Complex antioxidant defences exist within the host. They are distributed in body fluids and within various compartments of the cell. Plasma contains a wide range of substances with antioxidant properties. These include molecules derived directly from the diet, such as vitamin E and other tocopherols, vitamin C, β-carotene and cachectins, and proteins and peptides, such as glutathione, caeruloplasmin, albumin, and metallothionein, which are synthesized endogenously. Many of these substances act

Potential disadvantageous effects of high rates of nutrient delivery during infection and trauma

Anorexia is a major feature of the response to pro-inflammatory cytokines. Anorexia may be an unfortunate phenomenon associated with the metabolic changes induced by cytokines, or it may be an attempt to selectively avoid nutrients that might disadvantage the response of the host to pathogens.78 Experimental and observational data suggest that either possibility could be the case. Rats given IL-1 and a choice of casein, lard, or a mixture of sucrose and cornstarch, reduced intakes of the

Conclusions

The ability of patients to survive and recover from trauma and infection lies in the ability to prioritize physiological processes, particularly those processes that exert a large metabolic demand. Therefore, at various times throughout the life cycle metabolic processes become focused on achieving growth, the construction of placenta and fetus, the synthesis of milk components, wound healing, and the repulsion of an invasion by pathogens. For the infected individual, the marshalling of

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