Stressed to death: Implication of lymphocyte apoptosis for psychoneuroimmunology

https://doi.org/10.1016/S0889-1591(02)00062-4Get rights and content

Abstract

Psychological and physical stressors best exemplify the intercommunication of the immune and the nervous systems. It has been shown that stress significantly impacts leukocyte cellularity and immune responses and alters susceptibility to various diseases. While acute stress has been shown to enhance immune responses, chronic stress often leads to immunosuppression. Among many criteria examined upon exposure to chronic stress, the reduction in lymphocyte mitogenic response and lymphocyte cellularity are commonly assessed. We have reported that chronic restraint stress could induce lymphocyte reduction, an effect dependent on endogenous opioids. Interestingly, the effect of endogenous opioids was found to be exerted through increasing the expression of a cell death receptor, Fas, and an increased sensitivity of lymphocytes to apoptosis. Stress-induced lymphocyte reduction was not affected by adrenalectomy. In this review, based on available literature and our recent data, we will discuss the role of the hypothalamic–pituitary–adrenal axis and endogenous opioids and examine the mechanisms by which chronic stress modulates lymphocyte apoptosis.

Introduction

The effect of physical and psychological stress on the immune system has been noticed since the 1940s (Kiecolt-Glaser, McGuire, Robles, & Glaser, 2002). Various studies with different model systems have demonstrated that depending on the mood and duration, stress could either enhance or reduce immune function (Ader & Cohen, 1993). It is generally accepted that acute stress could improve the function of the immune system, while chronic stress often results in reduction of immune responses (Dhabhar & McEwen, 1997). It has been shown that acute stress-promoted immune responses are dependent on the hypothalamic–pituitary–adrenal (HPA) axis (Dhabhar & McEwen, 1999), while the mechanisms by which chronic stress exerts its effect remain controversial. Our studies have shown that chronic restraint stress-induced lymphocyte reduction occurs through endogenous opioid-mediated Fas expression, which in turn induces apoptosis (Yin et al., 1999, Yin et al., 2000). In this paper we will briefly review lymphocyte apoptosis and its role in the regulation of lymphocyte homeostasis and immune responses. Our particular attention will be focused on chronic stress-induced lymphocyte apoptosis and the mechanisms controlling this process.

Section snippets

Apoptosis and lymphocyte homeostasis

Apoptosis is an evolutionary conserved ‘cell suicide’ program present in all nucleated metazoan cells (Chinnaiyan & Dixit, 1996; Meier, Finch, & Evan, 2000). Despite its highly conserved nature, it is only recently that any of the molecular mechanisms underlying apoptosis have been identified (Rich, Watson, & Wyllie, 1999). Apoptosis is now known as an active cell death process characterized by the activation of proteases, auto-destruction of chromatin, nuclear condensation, cellular membrane

Fas (CD95/APO-1) and Fas ligand (FasL/CD95L)

Fas antigen is a type I membrane protein of 45 kDa that belongs to the tumor necrosis factor (TNF)/nerve growth factor receptor family (Itoh et al., 1991). It is expressed on a variety of cell types including activated T- and B cells, hepatocytes, and ovarian epithelial cells (Watanabe-Fukunaga et al., 1992). It is also detected in solid tumors of the breast, ovary, colon, prostate, and liver. Ligation of this molecule with specific antibodies or its natural ligand (FasL) usually induces rapid

Opioids and immunosuppression

Opiates are an old class of drugs derived from the milky latex of poppy of the opium poppy Papaver somniferum and have been used for centuries as analgesics. Morphine is the primary alkaloid in opium. Opioids have effects on perception of pain, consciousness, motor control, mood, and autonomic function, and often induce physical dependence or addiction (Kieffer & Evans, 2002). In the mid 1970s, scientists discovered the existence of an endogenous morphine-like substance, enkephalin, in the

Lymphocyte apoptosis induced by chronic stress

Various studies have clearly demonstrated that the immune system is very sensitive to either physiological or psychological stress. Stress has been demonstrated in both humans and animals to be immunomodulatory and alter the pathogenesis of tumor development, autoimmunity, and infectious diseases by influencing the onset, course, and outcome of the pathological processes (Rabin, Cohen, Ganguli, Lysle, & Cunnick, 1989). Although acute stress is generally believed to exert positive effects on the

The mechanisms

Bi-directional communication between the nervous and immune systems occurs through neuroendocrine mechanisms and interaction with lymphoid tissue. It is clear that psychological or physical stressors that activate these pathways can alter immunity and disease resistance. Many mechanisms have been proposed to account for stress-induced alterations in immunity, including changes in the lymphocytes signaling process, migration pattern, and viability. We will review the literature regarding cell

Summary

Chronic stress often leads to the suppression of the immune system. In this paper, we have summarized current literature related to stress-induced lymphocyte apoptosis under stress conditions. Based on available knowledge, stress induced-lymphocyte apoptosis does may play a prominent role in the pathogenesis of various diseases. Increasing evidence suggests that a compromised immune system may be a major contributor to cancer development and can impact the outcome of cancer therapies. We

Acknowledgements

This work was supported by research grants AI50222 and AI43384 from the National Institute of Health and Grant IIH 00208 from the National Space Biomedical Research Institute.

References (100)

  • L. McCarthy et al.

    Opioids, opioid receptors, and the immune response

    Drug Alcohol Depend.

    (2001)
  • B.S. McEwen et al.

    The role of adrenocorticoids as modulators of immune function in health and disease: Neural, endocrine, and immune interactions

    Brain Res. Brain Res. Rev.

    (1997)
  • M. Narita et al.

    Regulations of opioid dependence by opioid receptor types

    Pharmacol. Ther.

    (2001)
  • J. O’Connell et al.

    The Fas counterattack: Cancer as a site of immune privilege

    Immunol. Today

    (1999)
  • D.A. Padgett et al.

    Restraint stress slows cutaneous wound healing in mice

    Brain Behav. Immun.

    (1998)
  • S. Roy et al.

    Dynorphin blocks opioid inhibition of macrophage-colony stimulating factor-induced proliferation of bone marrow cells

    Eur. J. Pharmacol.

    (1991)
  • S. Roy et al.

    Chronic morphine treatment selectively suppresses macrophage colony formation in bone marrow

    Eur. J. Pharmacol.

    (1991)
  • S. Roy et al.

    Role of hypothalamic–pituitary axis in morphine-induced alteration in thymic cell distribution using μ-opioid receptor knockout mice

    J. Neuroimmunol.

    (2001)
  • M. Salzet et al.

    Crosstalk between nervous and immune systems through the animal kingdom: Focus on opioids

    Trends Neurosci.

    (2000)
  • K. Sharma et al.

    Death the Fas way: Regulation and pathophysiology of CD95 and its ligand

    Pharmacol. Ther.

    (2000)
  • G.B. Stefano

    Autoimmunovascular regulation: Morphine and anandamide and ancondamide stimulated nitric oxide release

    J. Neuroimmunol.

    (1998)
  • H.K. Sytwu et al.

    The roles of Fas/APO-1 (CD95) and TNF in antigen-induced programmed cell death in T cell receptor transgenic mice

    Immunity

    (1996)
  • T. Takahashi et al.

    Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand

    Cell

    (1994)
  • A.L. Vaccarino et al.

    Endogenous opiates: 1999

    Peptides

    (2000)
  • L.N. Wei et al.

    Regulation of opioid receptor expression

    Curr. Opin. Pharmacol.

    (2002)
  • E.P. Zorrilla et al.

    The relationship of depression and stressors to immunological assays: A meta-analytic review

    Brain Behav. Immun.

    (2001)
  • R. Ader et al.

    Psychoneuroimmunology: Conditioning and stress

    Annu. Rev. Psychol.

    (1993)
  • C.J. Barnes et al.

    Effect of aging on spontaneous and induced mouse testicular germ cell apoptosis

    Aging (Milano)

    (1998)
  • D. Bellgrau et al.

    A role for CD95 ligand in preventing graft rejection

    Nature

    (1995)
  • F. Berthiaume et al.

    Age- and disease-related decline in immune function: An opportunity for “thymus-boosting” therapies

    Tissue Eng.

    (1999)
  • P.J. Cabot

    Immune-derived opioids and peripheral antinociception

    Clin. Exp. Pharmacol. Physiol.

    (2001)
  • J.P. Capitanio et al.

    Psychosocial factors and disease progression in simian AIDS: A preliminary report

    AIDS

    (1991)
  • H.Y. Chang et al.

    Proteases for cell suicide: Functions and regulation of caspases

    Microbiol. Mol. Biol. Rev.

    (2000)
  • A.M. Chinnaiyan et al.

    The cell-death machine

    Curr. Biol.

    (1996)
  • M. Connor et al.

    Opioid receptor signalling mechanisms

    Clin. Exp. Pharmacol. Physiol.

    (1999)
  • B.L. Crabtree

    Review of naltrexone, a long-acting opiate antagonist

    Clin. Pharm.

    (1984)
  • G. Delogu et al.

    Apoptosis and surgical trauma: Dysregulated expression of death and survival factors on peripheral lymphocytes

    Arch. Surg.

    (2000)
  • G. Delogu et al.

    Mitochondrial perturbations and oxidant stress in lymphocytes from patients undergoing surgery and general anesthesia

    Arch. Surg.

    (2001)
  • F.S. Dhabhar et al.

    Stress-induced enhancement of antigen-specific cell-mediated immunity

    J. Immunol.

    (1996)
  • F.S. Dhabhar et al.

    Enhancing versus suppressive effects of stress hormones on skin immune function

    Proc. Natl. Acad. Sci. USA

    (1999)
  • L. Dominguez-Gerpe et al.

    Alterations induced by chronic stress in lymphocyte subsets of blood and primary and secondary immune organs of mice

    BMC Immunol.

    (2001)
  • D.O. Freier et al.

    Morphine-induced alterations in thymocyte subpopulations of B6C3F1 mice

    J. Pharmacol. Exp. Ther.

    (1993)
  • B.A. Fuchs et al.

    Morphine induces apoptosis in murine thymocytes in vivo but not in vitro: Involvement of both opiate and glucocorticoid receptors

    J. Pharmacol. Exp. Ther.

    (1993)
  • A. Gajdos

    Opiate receptors and their natural endogenous substrates. Enkephalins, endorphins

    Nouv. Presse Med.

    (1977)
  • A. Galinowski

    Stress and panic. Immunologic aspects

    Encephale

    (1993)
  • M. Girardi et al.

    Regulation of cutaneous malignancy by gammadelta T cells

    Science

    (2001)
  • D.R. Green et al.

    Fas-ligand: Privilege and peril

    Proc. Natl. Acad. Sci. USA

    (1997)
  • T.J. Grudt et al.

    Opioid receptors and the regulation of ion conductances

    Rev. Neurosci.

    (1995)
  • S.R. Hameroff

    Opiate receptor pharmacology: Mixed agonist/antagonist narcotics

    Contemp. Anesth. Pract.

    (1983)
  • H. Hug

    Fas-mediated apoptosis in tumor formation and defense

    Biol. Chem.

    (1997)
  • Cited by (73)

    • Chronic Social Stress Ameliorates Psoriasiform Dermatitis Through Upregulation of the Hypothalamic-Pituitary-Adrenal axis

      2018, Brain, Behavior, and Immunity
      Citation Excerpt :

      Therefore, psychosocial stress was found to worsen psoriasis only in the subjects who exhibited an impaired HPA axis response (Richards et al., 2005), as suggested by earlier studies (Thaller et al., 1999). This phenomenon of functional hypocortisolism in inflammatory diseases could be due to defects of the HPA-axis, altered glucocorticosteroid availability or glucocorticoid receptor dysfunctions (reviewed in Silverman and Sternberg (2012), Yang et al. (2012)). A number of studies applying similar social stress paradigms have shown, as also seen in humans (Cohen et al., 2012), the presence of glucocorticoid resistance (Fuertig et al., 2016; Sheridan et al., 2000), which implies an altered inhibitory feedback (Bartolomucci et al., 2004) driven by insensitivity to glucocorticoids and a heightened innate inflammatory signaling (Fuertig et al., 2016).

    View all citing articles on Scopus
    View full text