Pii: s0022-3999(02)00309-4

Journal of Psychosomatic Research 53 (2002) 873 – 876 Central pathways to morbidity and mortality Janice K. Kiecolt-Glasera,*, Ronald Glaserb aDepartment of Psychiatry, The Ohio State University College of Medicine, 1670 Upham Drive, Columbus, OH 43210, USA bDepartment of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University College of Medicine, Columbus, OH 43210, USA Objective: The increased morbidity and mortality associated periodontal disease, frailty, and functional decline. Additionally, with depression is substantial. In this paper, we review evidence depression can down-regulate the cellular immune response; as a suggesting that depression contributes to disease and death through consequence, processes such as prolonged infection and delayed immune dysregulation. Method: This review focuses on recent wound healing that fuel sustained proinflammatory cytokine human studies addressing the impact of depression on immune production may be promoted by depression. Conclusions: These function, and the health consequences of those changes. Results: direct and indirect processes pose the greatest health risks for older There is growing evidence that depression can directly stimulate the adults who already show age-related increases in proinflammatory production of proinflammatory cytokines that influence a spectrum cytokine production. Thus, aging interacts with depression to of conditions associated with aging, including cardiovascular enhance risks for morbidity and mortality. D 2002 Elsevier disease, osteoporosis, arthritis, type 2 diabetes, certain cancers, Keywords: Proinflammatory cytokines; Interleukin 6; Psychoneuroimmunology; Stress Depression is the most common psychiatric illness; both cytokines have substantial effects on the CNS, including major depression and subthreshold depressive symptoms production and enhancement of negative moods, physical carry substantial health risks, reviewed in the articles in this symptoms including lethargy and fatigue, and a range of issue of the journal and elsewhere [1 – 4]. Depression can sickness behaviors from shivering to loss of appetite affect health through many pathways; these influences may [8,10,11]. Indeed, despite our focus on the impact of occur through health behaviors or compliance with medical depression on immune responses and disease, there is also regimens, as well as through alterations in the functioning of plausible evidence that the immune system has a role in the the central nervous system (CNS), immune, endocrine, and neuroendocrine and behavioral features of both depressive cardiovascular systems [5 – 8]. In this paper, we consider how depression may contribute to morbidity and mortalitythrough immune dysregulation. We focus on a central immu-nological mechanism that serves as a gateway for a range of Morbidity, mortality, and aging: central immunological age-associated diseases, the dysregulation of proinflamma- tory cytokine production, particularly interleukin 6 (IL-6) [9].
Although we will not address the effects of disease on The immune system’s inflammatory response can be emotional distress in any detail, it is important to mention triggered in a variety of ways, including infection and the bidirectional nature of the relationship. Unquestionably, trauma. Inflammation is an important and constructiveconsequence of infection and injury; proinflammatory cyto-kines including IL-1, IL-6, and tumor necrosis factor (TNF)attract immune cells to the site of infection or injury, and * Corresponding author. Tel.: +1-614-292-0033; fax: +1-614-292-0038.
prime them to become activated to respond. Anti-inflam- E-mail addresses: [email protected] (J.K. Kiecolt-Glaser), matory cytokines such as IL-10 and IL-13 serve to dampen 0022-3999/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved.
PII: S 0 0 2 2 - 3 9 9 9 ( 0 2 ) 0 0 3 0 9 - 4 J.K. Kiecolt-Glaser, R. Glaser / Journal of Psychosomatic Research 53 (2002) 873–876 this immune response, including decreased cell function and alterations in immune responses to challenge under well- synthesis of other cytokines. Thus, broadly speaking, cyto- controlled conditions; accordingly, they serve as a proxy for kines provide intercellular signals that help to regulate the response to an infectious agent [26 – 29]. More distressed immune system’s response to injury and infection.
and more anxious individuals produce immune responses to Although the mechanisms associated with inflammation vaccines that are delayed, substantially weaker, and/or are critical to resolving infections and repairing tissue shorter lived [26 – 29]; as a consequence, it is reasonable damage, chronic or recurring infections can provoke patho- to assume these same individuals would also be slower to logical changes [12]. For example, low levels of persistent develop immune responses to pathogens; thus, they could be inflammation may result when chronic infectious processes at greater risk for more severe illness. Consistent with this such as periodontal disease, urinary tract infections, chronic argument, adults who show poorer responses to vaccines pulmonary disease, and chronic renal disease persistently also experience higher rates of clinical illness, as well as stimulate the immune system. Persistent stimulation of longer lasting infectious episodes [30]. In addition, other proinflammatory cytokine production has the greatest researchers have shown that distress can alter susceptibility impact among older adults who already show age-related to cold viruses [31]. Furthermore, distress also provokes substantial delays in wound healing [32,33], and enhancesthe risk for wound infection after injury [34].
Increased susceptibility to infectious disease and poorer recovery from infection are substantial and important prob-lems; in addition, however, they carry additional risks.
Depression enhances the production of proinflammatory Repeated, chronic, or slow-resolving infections or wounds cytokines, including IL-6 [14 – 18]. Importantly, both enhance secretion of proinflammatory cytokines, a process depressive symptoms and syndromal depression are associ- that can serve to further inhibit certain aspects of immune ated with heightened plasma IL-6 levels [16]. Following responses (e.g., IL-2, a cytokine important in protection successful pharmacologic treatment, elevated IL-6 levels against infection) [35]. Thus, depression can directly affect decline in patients with a major depression diagnosis [19].
the cells of the immune system and modulate the secretion Moreover, both physical and psychological stressors can of proinflammatory cytokines; in addition, depression may provoke transient increases in proinflammatory cytokines also contribute to prolonged or chronic infections or [20 – 22]; in animal models, both stress and administration delayed wound healing, processes that indirectly fuel proin- of epinephrine elevate plasma IL-6, consistent with evid- flammatory cytokine production. We next consider evid- ence that IL-6 production is stimulated through b-adrenergic ence which suggests that the etiology and course of a very receptors, among other pathways [23,24]. Thus, production broad range of diseases may be altered by dysregulated of IL-6 and other proinflammatory cytokines can be directly stimulated by negative emotions and stressful experiences,providing one direct pathway.
Overproduction of proinflammatory cytokines may lead Morbidity, mortality, and inflammatory immune to subsequent maladaptive immune and endocrine changes.
IL-6 is a potent stimulator of corticotropin-releasing hor-mone (CRH) production, a mechanism that leads to height- Inflammation has been linked to a spectrum of conditions ened HPA activity, including elevated levels of plasma associated with aging, including cardiovascular disease [9].
ACTH, followed by increased cortisol levels [14]; eleva- The association between cardiovascular disease and IL-6 is tions in ACTH and cortisol can provoke multiple adverse related in part to the central role that this cytokine plays in immunological changes [8]. The complexity of these poten- promoting the production of C-reactive protein (CRP), an tial interactions is further underscored by one line of important risk factor for myocardial infarction [23]. For research which suggests that once cortisol levels rise, they example, high concentrations of CRP predicted the risk of can initiate, perpetuate or aggravate syndromal depression, future cardiovascular disease in apparently healthy men depression-like behaviors, and depressive symptoms such as [36]. Further studies provided mechanistic links: chronic anxiety, insomnia, and poor memory [25]. Thus, negative infections amplified the risk for development of atheroscler- emotions that dysregulate IL-6 secretion may also promote osis fourfold in subjects who were free of carotid athero- sclerosis at baseline, conferring increased risk even in Indeed, in addition to their association with enhanced subjects lacking conventional vascular risk factors [37].
secretion of proinflammatory cytokines, depression and Indeed, the increased risk for artery-clogging plaque was distress can also have direct adverse effects on a variety greater than that conferred by elevated blood pressure or of other immunological mechanisms, including the down- cholesterol [37]. Cardiovascular disease is the leading cause regulation of cellular and humoral responses [8], and these of death, and individuals with high levels of both IL-6 and changes are large enough to be clinically significant. For CRP were 2.6 times more likely to die over a 4.6-year example, vaccine responses demonstrate clinically relevant period than those who had low levels of both [38].
J.K. Kiecolt-Glaser, R. Glaser / Journal of Psychosomatic Research 53 (2002) 873–876 In addition to cardiovascular disease, inflammation has dition to their ability to lower lipids [45]. Additionally, the use been linked to a spectrum of conditions associated with aging, of antidepressants can normalize activation of the inflammat- including osteoporosis, arthritis, type 2 diabetes, certain ory response system in patients with a major depression lymphoproliferative diseases and other cancers (including diagnosis [19]. The question of whether cognitive or other multiple myeloma, non-Hodgkin’s lymphoma, and chronic psychological treatments for depression have similar positive lymphocytic leukemia), Alzheimer’s disease, and periodontal consequences is an important arena for future research.
disease [9]. In fact, more globally, chronic inflammation hasbeen suggested as one key biological mechanism that mayfuel declines in physical function leading to frailty, disability, and, ultimately, death [12,39]. For example, elevated levels ofCRP and IL-6 predicted the development of type 2 diabetes in Many lines of evidence now indicate that IL-6 may a 4-year follow-up period in healthy women after adjustments function as a ‘‘. . .global marker of impending deterioration for BMI, family history of diabetes, smoking, exercise, in health status in older adults’’ (p. 645) [41]. Indeed, even alcohol, and hormone replacement therapy; among women after the point at which risk factors such as cholesterol, in the highest vs. lowest quartiles, the relative risk for hypertension, and obesity predict health deterioration less developing diabetes was 7.5 for IL-6 and 15.7 for CRP [40].
successfully among the very old, chronic inflammation In other work, elevated serum IL-6 levels predicted future continues to be an important marker [41]. We have argued disability in older adults, a finding that may reflect the effects that depression (both syndromal and subsyndromal) directly of the cytokine on muscle atrophy, and/or to the pathophy- prompts immune dysregulation, and these processes may siologic role played by the cytokine in particular diseases lead to subsequent maladaptive immune and endocrine [41]. Proinflammatory cytokines including IL-6 may slow changes [14,20 – 24]. Production of IL-6 and other proin- muscle repair following injury and accelerate muscle wast- flammatory cytokines can be directly stimulated by depres- ing [42]; indeed, IL-6 and CRP also play a pathogenic role in sion, providing one direct pathway. In addition, depression a range of diseases associated with disability among the and stress may also contribute to prolonged infection or elderly (osteoporosis, arthritis, and congestive heart failure, delayed wound healing, processes that fuel sustained proin- among others) [41]. In this context, it is interesting that IL-6 flammatory cytokine production. Thus, research that is also associated with self-rated health [43], a robust addresses the dysregulation of the immune and endocrine predictor of mortality [10]. Thus, the clinical importance of systems associated with depression could substantially immunological dysregulation for older adults is highlighted enhance our understanding of psychological influences on by increased risks across diverse conditions and diseases.
health, particularly among the elderly.
In addition to the direct influences of psychological states Work on this article was supported by NIH grants on physiological function, distressed individuals are more K02 MH01467, R37 MH42096, PO1 AG16321, M01-RR- likely to have health habits that put them at greater risk, including poorer sleep, a greater propensity for alcohol anddrug abuse, poorer nutrition, and less exercise, and thesehealth behaviors have cardiovascular, immunological, and endocrinological consequences [44]. Higher plasma IL-6and CRP levels are associated with adverse health habits: [1] Katz IR. On the inseparability of mental and physical health in aged values for both are higher in smokers than nonsmokers, in persons: lessons from depression and medical comorbidity. Am JGeriatr Psychiatry 1996;4:1 – 16.
individuals who report less physical activity, and in those [2] Penninx BWJH, Geerlings SW, Deeg DJH, van Eijk JTM, van Tilburg with a higher body mass index [39,41]. However, health W, Beekman ATF. Minor and major depression and the risk of death in habits including smoking, physical activity, and alcohol use older persons. Arch Gen Psychiatry 1999;56:889 – 95.
have typically explained only a small part of the excess [3] Penninx BWJH, Leveille S, Ferrucci L, van Eijk JTM, Guralnik JM.
mortality associated with depression among older adults Exploring the effect of depression on physical disability: longitudinalevidence from the established populations for epidemiologic studies of [3]. Similarly, IL-6 has robust relationships with morbidity the elderly. Am J Public Health 1999;89:1346 – 52.
and mortality, even after controlling for health behaviors [4] Wulsin LR. Does depression kill? Arch Intern Med 2000;160: [39 – 41]. Thus, health behaviors, although obviously im- portant, are not sufficient to explain the relationship be- [5] Carney RM, Freedland KE, Rich MW. Depression as a risk factor for cardiac events in established coronary heart disease: a review of pos-sible mechanisms. Ann Behav Med 1995;17:142 – 9.
Pharmacologic treatments hold promise. A prospective [6] Krantz DS, McCeney M. Do psychological and social factors have an trial of statins produced reductions in CRP, providing evid- impact on organic disease? A critical assessment of research on cor- ence that these drugs have anti-inflammatory effects in ad- onary heart disease. Annu Rev Psychol 2001;53:341 – 69.
J.K. Kiecolt-Glaser, R. Glaser / Journal of Psychosomatic Research 53 (2002) 873–876 [7] Davidson RJ, Jackson DC, Kalin NH. Emotion, plasticity, context, [25] Wolkowitz OM, Reus VI. Treatment of depression with antiglucocor- and regulation: perspectives from affective neuroscience. Psychol Bull ticoid drugs. Psychosom Med 1999;61:698 – 711.
[26] Kiecolt-Glaser JK, Glaser R, Gravenstein S, Malarkey WB, Sheridan [8] Miller AH. Neuroendocrine and immune system interactions in stress J. Chronic stress alters the immune response to influenza virus vaccine and depression. Psychiatr Clin North Am 1998;21:443 – 63.
in older adults. Proc Natl Acad Sci USA 1996;93:3043 – 7.
[9] Ershler W, Keller E. Age-associated increased interleukin-6 gene [27] Vedhara K, Cox NKM, Wilcock GK, Perks P, Hunt M, Anderson S, expression, late-life diseases, and frailty. Annu Rev Med 2000;51: Lightman SL, Shanks NM. Chronic stress in elderly carers of demen- tia patients and antibody response to influenza vaccination. Lancet [10] Leventhal H, Patrick-Miller L, Leventhal EA, Burns EA. Does stress- emotion cause illness in elderly people? In: Schaie KW, Lawton MP, [28] Glaser R, Kiecolt-Glaser JK, Bonneau RH, Malarkey W, Kennedy S, editors. Annual review of gerontology and geriatrics, vol. 17: focus Hughes J. Stress-induced modulation of the immune response to re- on emotion and adult development. New York, NY: Springer combinant hepatitis B vaccine. Psychosom Med 1992;54:22 – 9.
Publishing, 1998;vol. 17. pp. 138 – 84.
[29] Glaser R, Sheridan JF, Malarkey WB, MacCallum RC, Kiecolt-Glaser [11] Dantzer R, Wollman E, Vitkovic L, Yirmiya R. Cytokines and depres- JK. Chronic stress modulates the immune response to a pneumococcal sion: fortuitous or causative association? Mol Psychiatry 1999;4: pneumonia vaccine. Psychosom Med 2000;62:804 – 7.
[30] Burns EA, Goodwin JS. Immunology and infectious disease. In: Cas- [12] Hamerman D. Toward an understanding of frailty. Ann Intern Med sel CK, Riesenberg DE, Sorensen LB, editors. Geriatric medicine.
New York: Springer-Verlag, 1990. pp. 312 – 29.
[13] Cohen HJ. Editorial: in search of the underlying mechanisms of frailty.
[31] Cohen S, Frank E, Doyle WJ, Skoner DP, Rabin BS, Gwaltney JM.
J Gerontol, Ser A: Biol Sci Med Sci 2000;55:M706 – 8.
Types of stressors that increase susceptibility to the common cold in [14] Dentino AN, Pieper CF, Rao KMK, Currie MS, Harris T, Blazer DG, healthy adults. Health Psychol 1998;17:214 – 23.
Cohen HJ. Association of interleukin-6 and other biologic variables [32] Kiecolt-Glaser JK, Marucha PT, Malarkey WB, Mercado AM, Glaser with depression in older people living in the community. J Am Geriatr R. Slowing of wound healing by psychological stress. Lancet [15] Maes M, Bosmans E, De Jongh R, Kenis G, Vandoolaeghe E, Neels [33] Marucha PT, Kiecolt-Glaser JK, Favagehi M. Mucosal wound healing H. Increased serum IL-6 and IL-1 receptor antagonist concentrations is impaired by examination stress. Psychosom Med 1998;60:362 – 5.
in major depression and treatment resistant depression. Cytokine [34] Rojas I, Padgett DA, Sheridan JF, Marucha PT. Stress-induced sus- ceptibility to bacterial infection during cutaneous wound healing.
[16] Lutgendorf SK, Garand L, Buckwalter KC, Reimer TT, Hong S, Brain, Behav, Immun 2002;16:74 – 84.
Lubaroff DM. Life stress, mood disturbance, and elevated interleu- [35] Catania A, Airaghi L, Motta P, Manfredi MG, Annoni G, Pettenati C, kin-6 in healthy older women. J Gerontol, Ser A: Biol Sci Med Sci Brambilla F, Lipton JM. Cytokine antagonists in aged subjects and their relation with cellular immunity. J Gerontol, Ser A: Biol Sci Med [17] Maes M, Song C, Lin A, De JR, Van GA, Kenis G, Bosmans E, De MI, Benoy I, Neels H, Demedts P, Janca A, Scharpe S, Smith R. The [36] Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH.
effects of psychological stress on humans: increased production of Inflammation, aspirin, and the risk of cardiovascular disease in appa- pro-inflammatory cytokines and a Th1-like response in stress-induced rently healthy men. N Engl J Med 1997;336:973 – 9.
anxiety. Cytokine 1998;10:313 – 8.
[37] Kiechl S, Egger G, Mayr M, Wiedermann CJ, Bonora E, Oberhol- [18] Maes M, Lin A, Delmeire L, Van Gastel A, Kenis G, De Jongh R, lenzer F, Muggeo M, Xu Q, Wick G, Poewe W, Willeit J. Chronic Bosmans E. Elevated serum interleukin-6 (IL-6) and IL-6 receptor infections and the risk of carotid atherosclerosis: prospective results concentrations in posttraumatic stress disorder following accidental from a large population study. Circulation 2001;103:1064 – 70.
man-made traumatic events. Biol Psychiatry 1999;45:833 – 9.
[38] Harris T, Ferrucci L, Tracy R, Corti M, Wacholder S, Ettinger WJ, [19] Sluzewska A, Rybakowski JK, Laciak M, Mackiewicz A, Sobieska Heimovitz H, Cohen H, Wallace R. Associations of elevated interleu- M, Wiktorowicz K. Interleukin-6 serum levels in depressed patients kin-6 and C-reactive protein levels with mortality in the elderly. Am J before and after treatment with fluoxetine. Ann N Y Acad Sci [39] Taaffe DR, Harris TB, Ferrucci L, Rowe J, Seeman TE. Cross- [20] Song C, Kenis G, Van Gastel A, Bosmans E, Lin A, de Jong R, Neels sectional and prospective relationships of interleukin-6 and C-reactive H, Scharpe S, Janca A, Yasukawa K, Maes M. Influence of psycho- protein with physical performance in elderly persons: MacArthur logical stress on immune-inflammatory variables in normal humans: studies of successful aging. J Gerontol, Ser A: Biol Sci Med Sci Part II. Altered serum concentrations of natural anti-inflammatory agents and soluble membrane antigens of monocytes and T lympho- [40] Pradhan A, Manson J, Rifai N, Buring J, Ridker P. C-reactive protein, cytes. Psychiatry Res 1999;85:293 – 303.
interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA, [21] DeRijk R, Michelson D, Karp B, Petrides J, Galliven E, Deuster P, J Am Med Assoc 2001;286:327 – 34 (Jul 18).
Paciotti G, Gold PW, Sternberg EM. Exercise and circadian rhythm- [41] Ferrucci L, Harris T, Guralnik J, Tracy R, Corti M, Cohen H, Penninx induced variations in plasma cortisol differentially regulate interleu- B, Pahor M, Wallace R, Havlik R. Serum IL-6 level and the develop- kin-1b (IL-1b), IL-6, and tumor necrosis factor-a (TNF-a) production ment of disability in older persons. J Am Geriatr Soc 1999;47:639 – 46.
in humans: high sensitivity of TNF-a and resistance of IL-6. J Clin [42] Cannon J. Cytokines in aging and muscle homeostasis. J Gerontol, Ser Endocrinol Metab 1997;82:2182 – 92.
A: Biol Sci Med Sci 1995;50:120 – 3.
[22] Zhou D, Kusnecov AW, Shurin MR, DePaoli M, Rabin BS. Exposure [43] Cohen HJ, Pieper CF, Harris T, Rao KMK, Currie MS. The association to physical and psychological stressors elevates plasma interleukin 6: of plasma IL-6 levels with functional disability in community-dwelling relationship to the activation of hypothalamic-pituitary-adrenal axis.
elderly. J Gerontol, Ser A: Biol Sci Med Sci 1997;52:M201 – 8.
[44] Kiecolt-Glaser JK, Glaser R. Methodological issues in behavioral [23] Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP. The immunology research with humans. Brain, Behav, Immun 1988;2: pathophysiologic roles of interleukin-6 in human disease. Ann Intern [45] Albert M, Danielson E, Rifai N, Ridker P. Effect of statin therapy on [24] Karalis KP, Kontopoulos E, Muglia LJ, Majzoub JA. Corticotropin- C-reactive protein levels: the pravastatin inflammation/CRP evalua- releasing hormone deficiency unmasks the proinflammatory effect of tion (PRINCE): a randomized trial and cohort study. JAMA, J Am epinephrine. Proc Natl Acad Sci USA 1999;96:7093 – 7.
Med Assoc 2001;286:64 – 70 (Jul 4).

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