Review article
Cytokines and major depression

https://doi.org/10.1016/j.pnpbp.2004.11.003Get rights and content

Abstract

In the research field of psychoneuroimmunology, accumulating evidence has indicated the existence of reciprocal communication pathways between nervous, endocrine and immune systems. In this respect, there has been increasing interest in the putative involvement of the immune system in psychiatric disorders. In the present review, the role of proinflammatory cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-α and interferon (IFN)-γ, in the aetiology and pathophysiology of major depression, is discussed. The ‘cytokine hypothesis of depression’ implies that proinflammatory cytokines, acting as neuromodulators, represent the key factor in the (central) mediation of the behavioural, neuroendocrine and neurochemical features of depressive disorders. This view is supported by various findings. Several medical illnesses, which are characterised by chronic inflammatory responses, e.g. rheumatoid arthritis, have been reported to be accompanied by depression. In addition, administration of proinflammatory cytokines, e.g. in cancer or hepatitis C therapies, has been found to induce depressive symptomatology. Administration of proinflammatory cytokines in animals induces ‘sickness behaviour’, which is a pattern of behavioural alterations that is very similar to the behavioural symptoms of depression in humans. The central action of cytokines may also account for the hypothalamic–pituitary–adrenal (HPA) axis hyperactivity that is frequently observed in depressive disorders, as proinflammatory cytokines may cause HPA axis hyperactivity by disturbing the negative feedback inhibition of circulating corticosteroids (CSs) on the HPA axis. Concerning the deficiency in serotonergic (5-HT) neurotransmission that is concomitant with major depression, cytokines may reduce 5-HT levels by lowering the availability of its precursor tryptophan (TRP) through activation of the TRP-metabolising enzyme indoleamine-2,3-dioxygenase (IDO). Although the central effects of proinflammatory cytokines appear to be able to account for most of the symptoms occurring in depression, it remains to be established whether cytokines play a causal role in depressive illness or represent epiphenomena without major significance.

Introduction

From a psychoneuroimmunological perspective, the brain is no longer regarded as an immunopriviliged organ that is separated entirely from circulating immune cells by the blood–brain barrier (BBB) and displays reduced or altered immune responsivity. In the last decades, it has become clear that many interactions occur between neural, immune and neuroendocrine systems (Fig. 1; Plaut, 1987, Felten and Felten, 1991, Cserr and Knopf, 1992, Ader et al., 1995, McGeer and McGeer, 1995).

The concept of bidirectional communication between the immune system and the central nervous system (CNS) has led to the question whether the immune system, besides playing a role in normally occurring brain–immune interactions, is also involved in neuropathological processes (Miller et al., 1999). One of the psychiatric disorders that is assumed to be related to changes in the functional activity of the immune system, is major depression. Dysregulation of the functional activity of the immune system in depression is a phenomenon that has been demonstrated numerous times (Kronfol et al., 1983, Irwin and Gillin, 1987, Maes, 1995, Maes, 1999, Nunes et al., 2002). In 1999, Maes proposed the ‘IRS model of major depression’, which implies that major depression is related to activation of the inflammatory response system (IRS). According to this model, major depression may be considered a psychoneuroimmunological disorder, in which peripheral immune activation, through the release of proinflammatory cytokines, is responsible for the variety of behavioural, neuroendocrine and neurochemical alterations that are associated with this psychiatric condition. Besides the ‘IRS model of major depression’, this assumption has also been expressed as the ‘macrophage theory of depression’ (Smith, 1991, Leonard and Song, 1999, Leonard, 2001) and the ‘cytokine hypothesis of depression’ (Yirmiya et al., 1999). In this review, the latter expression is used.

In the present review, the nature of the interactions between cytokines, the CNS and the endocrine system, through modulation of monoaminergic neurotransmission and regulation of the activity of the hypothalamic–pituitary–adrenal (HPA) axis, is discussed. The elicitation of certain behavioural characteristics by proinflammatory cytokines (the so-called ‘sickness behaviour’) is also considered, as these behavioural features resemble the symptoms of depression. In addition, putative mechanisms and pathways for the mode of action of central cytokines in major depression are suggested. Finally, the possible implications that the present model of aetiology and pathophysiology of major depression might have for cytokine treatment in (cancer and hepatitis C) therapies and the use of antidepressants, are mentioned.

Section snippets

Cytokines and neuroimmunology

Cytokines comprise a heterogeneous group of messenger molecules that are produced by immunocompetent cells, such as lymphocytes and macrophages, in order to regulate immune responses. Although their specific biological activities may vary, two general categories of cytokines can be distinguished, i.e. proinflammatory and anti-inflammatory cytokines (Table 1). The former group consists of cytokines that are directly or indirectly involved in inflammatory processes, such as interleukin (IL)-1,

Immune activation in major depression

Although major depression has been associated with ex vivo downregulated T and B cell proliferation as well as reduced natural killer (NK) cell activity (Kronfol et al., 1983, Irwin and Gillin, 1987), in vivo systemic activation of cell-mediated immune responses has been reported (Maes, 1995). Characteristics of immune activation in depressive illness include increases in the numbers of circulating lymphocytes and phagocytic cells upregulated serum levels of indicators of activated immune cells

Cytokines and monoaminergic disorders

Major depression is characterised by disorders in NA and 5-HT neurotransmission (Schildkraut, 1965, Ressler and Nemeroff, 1999, Ressler and Nemeroff, 2000, Dursun et al., 2001). It has been hypothesised that immune activation may be causally related to these signalling disorders, as proinflammatory cytokines have been implicated in alterations in NA and 5-HT turnover in brain regions assumed to be involved in major depression, including the hypothalamus, hippocampus, amygdala and prefrontal

Antidepressants: do these drugs exert immune effects?

The cytokine hypothesis of depression suggests a key role for cytokines in the mediation of the pathophysiological characteristics of major depression. From this perspective, it is tempting to assume that the efficacy of antidepressants in the treatment of depressive disorders may, at least in part, rely on downregulation of proinflammatory cytokine synthesis. But do antidepressants indeed exert immunomodulatory effects?

Although it is well established that antidepressants are effective in

The cytokine hypothesis of depression: a critical discussion

In the present review, the ‘cytokine hypothesis of major depression’ has been elaborated. Various aspects concerning the assumed links between depressive illness and cytokine production have been discussed. Although accumulating evidence supports a role for immune activation, through the production of proinflammatory cytokines, in the aetiology and pathophysiology of depression, the cytokine hypothesis of depression is still debatable.

Conclusion

At present, despite the accumulating evidence in support of the ‘cytokine hypothesis of depression’, the exact role of cytokines in the mediation of depressive symptomatology remains to be identified. The question whether cytokines are causally involved in the aetiology of depression or represent immunological side effects of this disease, so far remains unsolved. In order to elucidate the functional role of low concentrations of cytokines on the onset and the duration of major depression, the

Acknowledgments

The authors would like to thank Brian Leonard for his critical remarks and helpful suggestions on earlier versions of this work.

References (125)

  • N. Castanon et al.

    Effects of antidepressants on cytokine production and actions

    Brain Behav. Immun.

    (2002)
  • S. Chandler et al.

    Matrix metalloproteinases, tumor necrosis factor and multiple sclerosis: an overview

    J. Neuroimmunol.

    (1997)
  • H.F. Cserr et al.

    Cervical lymphatics, the blood–brain barrier and the immunoreactivity of the brain: a new view

    Immunol. Today

    (1992)
  • R. De Beaurepaire

    Questions raised by the cytokine hypothesis of depression

    Brain Behav. Immun.

    (2002)
  • S.M. Dursun et al.

    An exploratory approach to the serotonergic hypothesis of depression: bridging the synaptic gap

    Med. Hypotheses

    (2001)
  • W.J. Friedman

    Cytokines regulate expression of the type 1 interleukin-1 receptor in rat hippocampal neurons and glia

    Exp. Neurol.

    (2001)
  • S. Hall et al.

    Investigating the effects and altereffects of naturally occurring upper respiratory tract illnesses on mood and performance

    Physiol. Behav.

    (1996)
  • M. Irwin et al.

    Impaired natural killer cell activity among depression patients

    Psychiatry Res.

    (1987)
  • Z. Kronfol et al.

    Impaired lymphocyte function in depressive illness

    Life Sci.

    (1983)
  • M. Kubera et al.

    The effect of chronic treatment with imipramine on the immunoreactivity of animals subjected to a chronic mild stress model of depression

    Immunopharmacology

    (1995)
  • B.E. Leonard

    The immune system, depression and the action of antidepressants

    Prog. Neuro-psychopharmacol. Biol. Psychiatry

    (2001)
  • M. Maes

    Evidence for an immune response in major depression: a review and hypothesis

    Prog. Neuro-psychopharmacol. Biol. Psychiatry

    (1995)
  • M. Maes et al.

    Increased plasma concentrations of interleukin-6, soluble interleukin-6 receptor, soluble interleukin-2 receptor and transferrin receptor in major depression

    J. Affect. Disord.

    (1995)
  • M. Maes et al.

    Depressive and anxiety symptoms in the early puerperium are related to increased degradation of tryptophan into kynurenine, a phenomenon which is related to immune activation

    Life Sci.

    (2002)
  • P.L. McGeer et al.

    The inflammatory response system of the brain: implications for therapy of Alzheimer and other neurodegenerative diseases

    Brain Res. Rev.

    (1995)
  • Z. Merali et al.

    Effects of interleukin-1β and mild stress on alterations of norepinephrine, dopamine and serotonin neurotransmission: a regional microdialysis study

    Brain Res.

    (1997)
  • J.E. Merrill et al.

    Inflammatory events at the blood brain barrier: regulation of adhesion molecules, cytokines, and chemokines by reactive nitrogen and oxygen species

    Brain Behav. Immun.

    (1997)
  • R. Mossner et al.

    Enhancement of serotonin transporter function by tumor necrosis factor alpha but not by interleukin-6

    Neurochem. Int.

    (1998)
  • N. Müller et al.

    Psychoneuroimmunology and the cytokine action in the CNS: implications for psychiatric disorders

    Prog. Neuro-psychopharmacol. Biol. Psychiatry

    (1998)
  • Y. Pollak et al.

    Behavioral aspects of experimental autoimmune encephalomyelitis (EAE)

    J. Neuroimmunol.

    (2000)
  • T. Pollmächer et al.

    Low levels of circulating inflammatory cytokines—do they affect human brain functions?

    Brain Behav. Immun.

    (2002)
  • S. Ramamoorthy et al.

    Regulation of human serotonin transporter by interleukin-1 beta

    Biochem. Biophys. Res. Commun.

    (1995)
  • K.J. Ressler et al.

    Role of norepinephrine in the pathophysiology and treatment of mood disorders

    Biol. Psychiatry

    (1999)
  • W.J. Riedel et al.

    Tryptophan, mood, and cognitive function

    Brain Behav. Immun.

    (2002)
  • M. Rothermundt et al.

    Inflammatory markers in major depression and melancholia

    J. Affect. Disord.

    (2001)
  • B. Sakic et al.

    Blunted sensitivity to sucrose in autoimmune MRL-1pr mice: a curve shift study

    Brain Res. Bull.

    (1996)
  • R.M. Sapolsky et al.

    The development of the glucocorticoid receptor in the rat limbic system: III. Negative-feedback regulation

    Brain Res.

    (1985)
  • R.S. Smith

    The macrophage theory of depression

    Med. Hypotheses

    (1991)
  • S. Abe et al.

    Effects of chronic administration of interferon alpha A/D on serotonergic receptors in rat brain

    Neurochem. Res.

    (1999)
  • F. Adams et al.

    Neuropsychiatric manifestations of human leukocyte interferon therapy in patients with cancer

    J. Am. Med. Assoc.

    (1984)
  • H. Anisman et al.

    Anhedonic and anxiogenic effects of cytokine exposure

  • W.A. Banks et al.

    Passage of cytokines across the blood–brain barrier

    Neuroimmunomodulation

    (1995)
  • W.A. Banks et al.

    Entry of blood-borne cytokines into the central nervous system: effects on cognitive processes

    Neuroimmunomodulation

    (2003)
  • E.C. Beattie et al.

    Control of synaptic strength by glial TNF-α

    Science

    (2002)
  • E.W. Bernton et al.

    Release of multiple hormones by a direct action of interleukin-1 on pituitary cells

    Science

    (1987)
  • S. Bonaccorso et al.

    Psychological and behavioural effects of interferon-alpha

    Curr. Opin. Psychiatry

    (2000)
  • S. Borgstrom et al.

    Human leukocyte interferon and cimetidine for metastatic melanoma

    N. Engl. J. Med.

    (1982)
  • C.D. Breder et al.

    Interleukin-1 immunoreactive innervation of the human hypothalamus

    Science

    (1988)
  • C.A. Breder et al.

    Distribution and characterization of tumor necrosis factor-alpha-like immunoreactivity in the murine and central nervous system

    J. Comp. Neurol.

    (1993)
  • A.E. Calogero et al.

    Catecholamine effects upon rat hypothalamic corticotropin-releasing hormone secretion in vivo

    J. Clin. Invest.

    (1988)
  • Cited by (0)

    View full text