The inflammatory response is an integral part of the stress response: Implications for atherosclerosis, insulin resistance, type II diabetes and metabolic syndrome X

doi:10.1016/S0889-1591(03)00048-5

Brain, Behavior, and Immunity

Volume 17, Issue 5, October 2003, Pages 350-364

https://doi.org/10.1016/S0889-1591(03)00048-5 Get rights and content

Abstract

In previous publications, we presented the hypothesis that repeated episodes of acute or chronic psychological stress could induce an acute phase response (APR) and subsequently a chronic inflammatory process such as atherosclerosis. In this paper, that hypothesis, namely that such stress can induce an APR and inflammation, has been extended to include a chronic inflammatory process(s), characterized by the presence of certain cytokines and acute phase reactants (APR), which is associated with certain metabolic diseases. The loci of origin of these cytokines, particularly interleukin 6 (IL-6), and their induction, has been considered. Evidence is presented that the liver, the endothelium, and fat cell depots are the primary sources of cytokines, particularly IL-6, and that IL-6 and the acute phase protein (APP), C-reactive protein (CRP), are strongly associated with, and likely play a dominant role in, the development of this inflammatory process which leads to insulin resistance, non-insulin dependent diabetes mellitus type II, and Metabolic syndrome X. The possible role of psychological stress and the major stress-related hormones as etiologic factors in the pathogenesis of these metabolic diseases, as well as atherosclerosis, is discussed. The fact that stress can activate an APR, which is part of the innate immune inflammatory response, is evidence that the inflammatory response is contained within the stress response or that stress can induce an inflammatory response. The evidence that the stress, inflammatory, and immune systems all evolved from a single cell, the phagocyte, is further evidence for their intimate relationship which almost certainly was maintained throughout evolution.

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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The inflammatory response is an integral part of the stress response: Implications for atherosclerosis, insulin resistance, type II diabetes and metabolic syndrome X

Abstract

Introduction

Section snippets

Definition of stress

The induction of the acute phase response (APR)

IL-6 and the APR

Sources of IL-6

Macrophages and Kupffer cells of the liver

NIDDM and metabolic syndrome X

Stress and obesity

Stress and the APR

Innate immunity

Infections agent(s) as cause of long term cytokine-mediated APR

Coevolution of the stress and inflammatory processes

Discussion and conclusions

Acknowledgments

Immunol. Today

Brain Behav. Immun.

J. Psychosomatic Res.

Cytokine

Am. J. Cardiol.

J. Surg. Res.

Med. Hypotheses

Trends Immunol.

Curr. Opin. Immunol.

Med. Hypotheses

J. Neuroimmunol.

Brain Res.

Progr. Neurobiol.

Domes. Anim. Endocrinol.

J. Surg. Res.

Pathology

Molecular biology of macrophage activation: A pathway whereby psychological factors can potentially affect health

Psychosom. Med.

Randomized secondary prevention trial of azithromycin in patients with coronary artery disease and serological evidence for Chlamydia pneumoniae infection: the azithromycin in coronary artery disease: Elimination of myocardial infection with Chlamydia (ACADEMIC) study

Circulation

Failure to detect Chlamydia pneumoniae in calcific and degenerative atherosclerotic aortic valves excised during open heart surgery

APMIS

Role of β1- and β3-adrenoreceptors in the regulation of lipolysis and thermogenesis in rat brown adipocytes

Am. J. Physiol.

Fetal origins of coronary heart disease

BMJ

Association of serology with the endovascular presence of Chlamydia pneumoniae and Cytomegalovirus in coronary artery and vein graft disease

Circulation

Salmonellosis: A review of some unusual aspects

NEJM.

Stress and inflammation

Bacterial translocation from the gastrointestinal tract

J. Med.

Inflammatory cytokines impair endothelium-dependent dilation in human veins in vivo

Circulation

Need to test the arterial inflammation hypothesis

Circulation

Turning down insulin signaling

J. Clin. Invest.

Visceral fat accumulation: The missing link between psychosocial factors and cardiovascular disease

J. Intern. Med.

Abdominal obesity and the metabolic syndrome

Ann. Med.

Hypothalamic origin of the metabolic syndrome X

Ann. N. Y. Acad. Sci.

Hypothalamic arousal, insulin resistance and Type 2 diabetes mellitus

Diabetes Med.

Cytokines and fever

Ann. N. Y. Acad. Sci.

Is leptin a stress related peptide?

Nat. Med.

In vivo resistance of lipolysis to epinephrine. A new feature of childhood onset obesity

J. Clin. Invest.

Possible connections between stress, diabetes, obesity, hypertension and altered lipoprotein metabolism that may result in atherosclerosis

Clin. Sci.

Social inequality in coronary risk: Central obesity and the metabolic syndrome. Evidence from the Whitehall II study

Diabetologia

Internalized racism, body fat distribution, and abnormal fasting glucose among African-Caribbean women in Dominica West Indies

J. Nat. Med. Assoc.

Insulin is a prominent modulator of the cytokine-stimulated expression of acute-phase plasma protein genes

Mol. Cell. Biol.

Blood pressure and inflammation in apparently healthy men

Hypertension.