The inflammatory response is an integral part of the stress response: Implications for atherosclerosis, insulin resistance, type II diabetes and metabolic syndrome X
Introduction
In recent publications, we presented the hypothesis that repeated episodes of acute or chronic psychological stress can induce a chronic inflammatory process which may result in inflammatory disease (Black, 2002; Black and Berman, 1999; Black and Garbutt, 2002; see also Goodkin and Appels, 1997; Kop and Cohen, 2001 for reviews). We emphasized atherosclerosis, particularly coronary artery disease (CAD), since overwhelming evidence indicates that atherosclerosis is the result of a chronic inflammatory process (40–50% of patients with CAD do not have established CAD risk factors Black and Garbutt, 2002; Fahdi et al., submitted to BBI). Our hypothesis indicated that the major stress hormones (e.g., the catecholamines, corticosteroids, renin, growth hormone and glucagon) can induce an acute phase response (APR) which is similar to the response elicited when an organism reacts to an invading microorganism or sustains trauma and tissue injury.
In this paper, the hypothesis will be extended and the mechanism of cytokine production, as well as their loci of origin, will be considered. These loci include the liver, the endothelium, fat cell depots, and other organs/tissues (e.g., brain, adrenal gland, fibroblast, etc.). In particular, the effect of stress on interleukin 6 (IL-6) production from the endothelium and fat cells, as well as the development of insulin resistance, non-insulin dependent diabetes mellitus type II (NIDDM), Metabolic syndrome X, and innate immunity, will be examined. Last, the coevolution of the stress and inflammatory processes will be considered as further evidence of the linkage of the stress and inflammatory responses. In certain organs such as the endothelium and particular fat cell depots, and in syndromes such as NIDDM and Metabolic syndrome X, there is evidence of an inflammatory process. The argument that stress is a factor in the pathogenesis of these inflammatory processes will be put forth.
Section snippets
Definition of stress
Stress has been defined as a state of threatened homeostasis provoked by a psychological, environmental or physiological stressor (Chrousos and Gold, 1992; Peterson et al., 1991). One can define a stressor as a stimulus, either internal or external, that activates the hypothalamic pituitary adrenal (HPA) axis and the sympathetic nervous system (SNS), resulting in a physiological change or adaptation so that the organism can deal with the threat (Maier and Watkins, 1998). In addition to these
The induction of the acute phase response (APR)
The body responds to any type of tissue damage and infection with a series of specific physiological reactions in its attempt to repair the damage, contain the offending organism(s), promote wound healing, and recruit host defense mechanisms such as the innate immune response. These reactions are called the APR. A number of proteins, called acute phase proteins (APPs), are induced in the liver. These may be “positive” APPs (upregulated) or “negative” APPs (downregulated) in response to injury
IL-6 and the APR
Several lines of evidence indicate that IL-6 is the central mediator of the APR (see Heinrich et al., 1990 for review). For example, IL-6 knockout mice have an impaired APR (Inui, 2001). IL-1 and TNFα can induce IL-6 (McCarty, 1999). IL-1 knockout mice do not develop appreciable IL-6 and also have a diminished APR response (Zheng, 1995). In addition, IL-6 administered to humans subcutaneously induces an APR (McCarty, 1999). Two important APP, CRP and fibrinogen, have IL-6 response elements in
Sources of IL-6
The macrophage and cells with macrophage properties (e.g., Kupffer cells) are a source of IL-6. Other important sources of IL-6 are endothelial cells and fat cells. These sources of IL-6 will be considered in detail. IL-6 may also be synthesized in the brain, fibroblasts, smooth muscle cells, anterior pituitary cells (Deak et al., 1997), keratinocytes (Heinrich et al., 1990) and cells of the adrenal cortex (zona glomerulosa) (Judd et al., 1990).
Macrophages and Kupffer cells of the liver
In a previous publication, we postulated that stress may lead to the induction of cytokines1 from the Kupffer cells of the reticuloendothelial system (RES) which line the portal sinusoids of the liver. Endotoxin (lipopolysaccharide, (LPS)) which originated in the gastrointestinal tract (Black and Garbutt, 2002), and is a potent inducer of cytokines from cells of macrophage lineage (including Kupffer cells), is believed to
NIDDM and metabolic syndrome X
NIDDM and Metabolic syndrome X are closely related syndromes. Both diseases are characterized by abdominal obesity, insulin resistance, increased fasting blood glucose, dyslipidemia, hypertension, and accelerated atherosclerosis (Pickup et al., 1997; Pickup and Crook, 1998). A complete type II diabetes syndrome would be characterized by enhanced coagulation, diminished sex steroids with abnormalities in reproduction, increased capillary permeability, changes in metal ion metabolism, and
Stress and obesity
The relationship between cytokines and fat depots has been considered. Innervation of adipose tissue also affects its metabolic activity (Cousin et al., 1993) in that disturbances of the SNS are involved in the development of obesity in experimental animals and man (Tataranni, 1998). Catecholamines are lipolytic and increase triglyceride hydrolysis in various adipose depots, activate the expression of mitochondrial uncoupling proteins, and inhibit adipocyte proliferation (Lafontan et al., 1997,
Stress and the APR
In primate models, psychosocial stress may lead to depression, visceral obesity, increased adrenal size with a depression of dexamethasone inhibition, diminished sex steroid, and early signs of type II diabetes, the Metabolic syndrome X as well as CAD (Jayo et al., 1993; Shivley et al., 1997). In cynomolgus monkeys, the stress of social subordination leads to insulin resistance with hyperglycemia, increased central fat deposition, dyslipidemia, and hypertension. This syndrome is essentially the
Innate immunity
The immune system is based on two distinct recognition systems: innate and adaptive. The innate system does not utilize T and B lymphocytes, is ancient (preceding the development of the adaptive immune response) and is the first line of defense against invading organisms. Innate host defenses are found in all multicellular organisms whereas the adaptive immune system is found only in vertebrates. The innate immune system precedes and is essential for the adaptive immune response. It recognizes
Infections agent(s) as cause of long term cytokine-mediated APR
Inflammatory processes always raise questions as to their etiology. More specifically, is an infectious organism the etiologic factor? To our knowledge, no organism(s) has been isolated from the inflammatory processes or metabolic syndromes described herein. The vast majority of studies have concerned a possible infectious agent in atherosclerosis which is due to an inflammatory process and which we shall now consider.
Coevolution of the stress and inflammatory processes
The contention herein is that the inflammatory response is an integral part of the stress response. This section indicates that these responses coevolved. In invertebrates, and both lower and higher vertebrates, a common pool of highly conserved molecules mediates phagocytosis, the stress response and inflammation (see Ottaviani and Franceschi, 1996, Ottaviani and Franceschi, 1998 for reviews). A single cell, the “macrophage,” a phagocyte immunocyte is involved in all these processes. It is
Discussion and conclusions
From the studies reviewed, it is evident that a chronic inflammatory process associated with the vascular system is present. It is the result of activation of an APR with the production of APP; the presence of IL-6 is the prime mediator of the former, while CRP was the most common APP associated with the inflammatory process. Although IL-6 is the main mediator of the APR, corticosteroids and catecholamines are also likely to be involved (see Black and Garbutt, 2002 for review). Corticosteroids
Acknowledgments
The author would like to thank Dr. Willem J. Kop for reviewing the manuscript and Theresa Singleton, a graduate student in the Department of Microbiology, for her very valuable and essential assistance in the preparation of this manuscript.
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