Trends in Immunology
Volume 24, Issue 8, August 2003, Pages 444-448
Journal home page for Trends in Immunology

How stress influences the immune response

https://doi.org/10.1016/S1471-4906(03)00173-XGet rights and content

Abstract

In response to a stressor, physiological changes are set into motion to help an individual cope with the stressor. However, chronic activation of these stress responses, which include the hypothalamic–pituitary–adrenal axis and the sympathetic–adrenal–medullary axis, results in chronic production of glucocorticoid hormones and catecholamines. Glucocorticoid receptors expressed on a variety of immune cells bind cortisol and interfere with the function of NF-κB, which regulates the activity of cytokine-producing immune cells. Adrenergic receptors bind epinephrine and norepinephrine and activate the cAMP response element binding protein, inducing the transcription of genes encoding for a variety of cytokines. The changes in gene expression mediated by glucocorticoid hormones and catecholamines can dysregulate immune function. There is now good evidence (in animal and human studies) that the magnitude of stress-associated immune dysregulation is large enough to have health implications.

Section snippets

HPA axis and glucocorticoid hormones

The hypothalamus receives and monitors information about the environment and coordinates responses through nerves and hormones. Visual information, smell, hearing, temperature sensation and pain alert the hypothalamus to emergencies or environmental hazards. The emotional portions of the brain also relay information to the hypothalamus. From this integrative center, the brain controls hormone secretion from the pituitary gland and other tissues, such as the adrenal glands. For example,

Mechanisms of action for GC hormones

Being lipophilic molecules, GC hormones readily pass through the plasma membrane of all cells in the body. If a cell possesses a GC receptor (GR), that cell can be a target for action. There are two receptors for GC hormones, the GR and the mineralocorticoid receptor (MR). Because corticosterone has a higher affinity for MR than for GR [24], at low circulating levels glucocorticoid hormones bind preferentially to MR. Only at high circulating or tissue levels (i.e. during stress) is the GR

Sympathetic nervous system, adrenal medulla and catecholamines

In addition to regulation of immune function by glucocorticoid hormones associated with distress, it is known that catecholamines also modulate a range of immune functions, including cell proliferation, cytokine and antibody production, cytolytic activity and cell trafficking (reviewed in Refs 1, 45, 46). Catecholamines often act in concert with activation of the HPA axis. For example, paralleling the increase of GC-hormone production from the adrenal cortex, activation of the HPA axis also

Mechanism of action for catecholamines

Catecholamines mediate their effect on target tissues through adrenergic receptors and numerous cells of the immune system, including lymphocytes and macrophages, express adrenoreceptors. These are G-protein coupled receptors that can be divided into two subgroups, the α- and β-adrenergic receptors. It appears that the most important receptor for the immune system is the β2-adrenergic receptor [46]. β-adrenergic receptors function as intermediaries in transmembrane signaling pathways that

Conclusions

This Review has focused on GC hormones and catecholamines as the two major mediators of the stress effects on immune responses. However, other physiologic pathways are undoubtedly involved in the interplay. For example, endogenous opioids have recently been shown to diminish NK-cell cytotoxicity. In addition, a neuropeptide, substance P, is able to reduce inflammatory responses by suppressing IL-16 production by eosinophils. Whereas the focus of the anti-inflammatory effects of GC center on

Acknowledgements

This research was supported in part by NIH grants P50 DE13749 and PO1 AG16321, MH42096 MERIT AWARD, NIH General Clinical Research Center Grant MO1-RR-0034, and Ohio State University Comprehensive Cancer Center Core Grant CA16058.

References (55)

  • R.H. DeRijk

    Glucocorticoid receptor variants: clinical implications

    J. Steroid Biochem. Mol. Biol.

    (2002)
  • B. Marchetti

    Stress, the immune system and vulnerability to degenerative disorders of the central nervous system in transgenic mice expressing glucocorticoid receptor antisense RNA

    Brain Res. Brain Res. Rev.

    (2001)
  • W. Hoeck et al.

    Hormone-dependent phosphorylation of the glucocorticoid receptor occurs mainly in the amino-terminal transactivation domain

    J. Biol. Chem.

    (1990)
  • J. La Baer et al.

    Analysis of the DNA-binding affinity, sequence specificity and context dependence of the glucocorticoid receptor zinc finger region

    J. Mol. Biol.

    (1994)
  • K.C. Kanelakis

    Nucleotide binding states of hsp70 and hsp90 during sequential steps in the process of glucocorticoid receptor hsp90 heterocomplex assembly

    J. Biol. Chem.

    (2002)
  • K.J. Howard

    Mapping the HSP90 binding region of the glucocorticoid receptor

    J. Biol. Chem.

    (1990)
  • J.M. Berg

    DNA binding specificity of steroid receptors

    Cell

    (1989)
  • T.G. Hofmann

    Various glucocorticoids differ in their ability to induce gene expression, apoptosis and to repress NF-κB-dependent transcription

    FEBS Lett.

    (1998)
  • M.J. Schaaf et al.

    Molecular mechanisms of glucocorticoid action and resistance

    J. Steroid Biochem. Mol. Biol.

    (2002)
  • K.A. Sheppard

    Nuclear integration of glucocorticoid receptor and nuclear factor-κB signaling by CREB-binding protein and steroid receptor coactivator-1

    J. Biol. Chem.

    (1998)
  • V.M. Sanders et al.

    Sympathetic nervous system interaction with the immune system

    Int. Rev. Neurobiol.

    (2002)
  • K.S. Madden

    Catecholamines, sympathetic innervation, and immunity

    Brain Behav. Immun.

    (2003)
  • G.A. Carrasco et al.

    Neuroendocrine pharmacology of stress

    Eur. J. Pharmacol.

    (2003)
  • W.F. Simonds

    G protein regulation of adenylate cyclase

    Trends Pharmacol. Sci.

    (1999)
  • S. Barradeau

    Intracellular targeting of the type-I α regulatory subunit of cAMP-dependent protein kinase

    Trends Cardiovasc. Med.

    (2002)
  • B.S. Rabin

    Stress, Immune Function, and Health: The Connection

    (1999)
  • K.S. Madden et al.

    Catecholamine action and immunologic reactivity

  • Cited by (770)

    View all citing articles on Scopus
    View full text