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) .
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 . 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 . 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 . Furthermore, distress also provokes
substantial delays in wound healing [32,33], and enhancesthe risk for wound infection after injury .
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 . Following
responses (e.g., IL-2, a cytokine important in protection
successful pharmacologic treatment, elevated IL-6 levels
against infection) . Thus, depression can directly affect
decline in patients with a major depression diagnosis .
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 .
ACTH, followed by increased cortisol levels ; 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 . 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 . 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
. Further studies provided mechanistic links: chronic
anxiety, insomnia, and poor memory . 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 .
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 . Cardiovascular disease is the leading cause
regulation of cellular and humoral responses , 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 .
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 . 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 . 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 . 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) . 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 .
successfully among the very old, chronic inflammation
In other work, elevated serum IL-6 levels predicted future
continues to be an important marker . 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
. 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 ; 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) . In this context, it is interesting that IL-6
flammatory cytokine production. Thus, research that
is also associated with self-rated health , a robust
addresses the dysregulation of the immune and endocrine
predictor of mortality . 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 . Higher plasma IL-6and CRP levels are associated with adverse health habits:
 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
 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
 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
. 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
 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-
 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
 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
 Davidson RJ, Jackson DC, Kalin NH. Emotion, plasticity, context,
 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.
 Kiecolt-Glaser JK, Glaser R, Gravenstein S, Malarkey WB, Sheridan
 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.
 Ershler W, Keller E. Age-associated increased interleukin-6 gene
 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
 Leventhal H, Patrick-Miller L, Leventhal EA, Burns EA. Does stress-
emotion cause illness in elderly people? In: Schaie KW, Lawton MP,
 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.
 Glaser R, Sheridan JF, Malarkey WB, MacCallum RC, Kiecolt-Glaser
 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.
 Burns EA, Goodwin JS. Immunology and infectious disease. In: Cas-
 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.
 Cohen HJ. Editorial: in search of the underlying mechanisms of frailty.
 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
 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
 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
 Maes M, Bosmans E, De Jongh R, Kenis G, Vandoolaeghe E, Neels
 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
 Rojas I, Padgett DA, Sheridan JF, Marucha PT. Stress-induced sus-
ceptibility to bacterial infection during cutaneous wound healing.
 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-
 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
 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
 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.
 Kiechl S, Egger G, Mayr M, Wiedermann CJ, Bonora E, Oberhol-
 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.
 Harris T, Ferrucci L, Tracy R, Corti M, Wacholder S, Ettinger WJ,
 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
 Taaffe DR, Harris TB, Ferrucci L, Rowe J, Seeman TE. Cross-
 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-
 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,
 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-
 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
 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.
 Zhou D, Kusnecov AW, Shurin MR, DePaoli M, Rabin BS. Exposure
 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.
 Kiecolt-Glaser JK, Glaser R. Methodological issues in behavioral
 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
 Albert M, Danielson E, Rifai N, Ridker P. Effect of statin therapy on
 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).
los materiales impresos proponen. Y si el trabajo puede iniciarse supo-niendo que la tradicionalización de un romance de ciego ha de estu-diarse comparando un original con las versiones recogidas de la tradi-ción oral para documentar estados múltiples de cambio diacrónico, nadade esto obliga a asumir que la moral predicada, “el mensaje que coneste tipo de ‘fábulas’ se trata de transmiti