The current issue of Acta Neuropsychiatrica presents a series of papers which together provide a broad overview relating stress, immunity, cytokine activity and depressive illness, as well as the influence of cytokines on other neurological disorders. This introduction to the issue presents a broad perspective of the impact of stressors on immune functioning in animal studies and in humans, considering the potential effects of acute, subchronic and chronic stressors, as well as the contribution of previous stressor experience in promoting neurochemical and immunological alterations. Given the supposition that cytokines may act as immunotransmitters, and immune challenge may be viewed as a stressor, a brief review is provided concerning the impact of stressors and cytokine challenges on central neurochemical functioning, with particular emphasis on the commonalties between the effects of these treatments. It is suggested that by virtue of the neurochemical changes imparted by cytokines, a depressive affect may be instigated, just as it is in response to psychogenic stressors. To this end, an overview is presented concerning the relationship between cytokines and depression, as well as the influence of cytokine treatments on behavioral changes in animal studies and among patients receiving immunotherapy. Provisionally, the data support the view that activation of the inflammatory response system may contribute to affective illness, and that cytokines may act as signaling molecules to activate central nervous system processes regulating mood states.

Cytokines (e.g. various interleukins and subfamily members, tumor necrosis factors, interferons, chemokines and growth factors) act in the brain as immunoregulators and neuromodulators. Over a decade ago, the integrative article ‘Immunoregulators in the Nervous System’ (Neurosci Biobehav Rev 1991; 15: 185–215) provided a comprehensive framework of pivotal issues on cytokines and the nervous system that recently have been extensively studied. Cytokine profiles in the brain, including cytokine generation and action, have been studied in multiple models associated with neuropathophysiological conditions. These include: (1) acute conditions and disorders such as stroke (cerebral ischemia or infarction and intracranial hemorrhage), traumatic brain injury, spinal cord injury and acute neuropathies; (2) chronic neurodegenerative disorders and chronic conditions, including Alzheimer's disease, Parkinson's disease, neuropathic pain, epilepsy and chronic neuropathies; (3) brain infections, including bacterial meningitis and encephalitis; (4) brain tumors; (5) neuroimmunological disorders per se, such as multiple sclerosis; (5) psychiatric disorders, including schizophrenia and depression; (6) neurological and neuropsychiatric manifestations associated with non- central nervous system (CNS) disorders such as peripheral cancer, liver, kidney and metabolic compromise, and peripheral infectious and inflammatory conditions; and (7) cytokine immunotherapy, which can be accompanied by neuropsychiatric manifestations when administered either via peripheral or brain routes. Cytokine profiles have also been studied in multiple animal models challenged with inflammatory, infectious, chemical, malignant and stressor insults. Essentially data show that cytokines play a pivotal role in multiple neuropathophysiological processes associated with different types of disorders and insults. Cytokine expression and action in the brain shows a different profile across conditions, but some similarities exist. Under a defined temporal sequence, cytokine involvement in neuroprotection or the induction of a deleterious pathophysiological cascade and in resolution/healing is proposed depending on the type of cytokine. In the brain, functional interactions among cytokines, balance between pro-inflammatory and anti-inflammatory cytokines and functional interactions with neurotransmitters and neuropeptides play a pivotal role in the overall cytokine profile, pattern of neuropathophysiological cascades, and quality and magnitude of neuropsychiatric manifestations. In this brief review various selected cytokine-related issues with relevance to the brain are discussed.

The present paper reviews recent studies on the effects of stress on immune function in laboratory animals. The emphasis is on those studies where a simultaneous comparison of acute and chronic stress regimens was determined, although additional relevant studies are also reviewed. The effects of stress on basic measurements of cellular and humoral immune measures are discussed, including the growing number of studies that have reported alterations in macrophage functions. The latter are key elements in the innate immune response, and like measurements of T cell function and antibody production, are inhibited and enhanced by stressor exposure. This review does not focus on the mechanisms by which stress alters immune function, there being little to add conceptually in terms of what was reported previously (see Kusnecov AW, Rabin BS, Int Arch Allergy Immunol 1994;105:107–121.). However, a question is raised in the conclusion as to how stressor effects on immune function should be interpreted, for it is clear that immunological processes in and of themselves elicit central nervous system responses that neurochemically and endocrinologically do not differ from those produced in response to psychological stressors. Therefore, at least in the short term stressor-induced immune changes may not necessarily reflect maladaptive adjustments, although, as demonstrated by some studies reviewed in this paper, they may pose a serious risk to health should stressor exposure be persistent and uncontrolled.

Early life environmental factors have been associated with altered predisposition to a variety of pathologies. A considerable literature examines pre- and postnatal factors associated with increased risk of cardiovascular, metabolic (i.e. insulin resistance, hyperlipidemia) and psychiatric disease, and the importance of hormonal programming. The brain is exquisitely sensitive to environmental inputs during development and the stress responsiveness of the hypothalamic–pituitary–adrenal (HPA) axis has been shown to be both up- and down-regulated by early life exposure to limited nutrition, stress, altered maternal behaviors, synthetic steroids and inflammation. It has been suggested that peri-natal programming of HPA axis regulation might therefore contribute to metabolic and psychiatric disease etiology. In addition, glucocorticoids play modulatory roles regulating many aspects of immune function, notably controlling both acute and chronic inflammatory responses. Neuroendocrine–immune communication is bidirectional, and therefore it is expected that environmental factors altering HPA regulation have implications for stress effects on immune function and predisposition to inflammation. The impact of pre- and postnatal factors altering immune function, stress responsivity and predisposition to inflammatory disease are reviewed. It is also examined whether the early ‘immune environment’ might similarly influence predisposition to disease and alter neuroendocrine function. Evidence indicating a role for early life inflammation and infection as an important factor programming the neuroendocrine–immune axis and altering predisposition to disease is considered.

Activity of locus coeruleus (LC) neurons, the major noradrenergic cell-body group in the brain whose axons give rise to approximately 70% of norepinephrine (NE) in the brain, is believed to play an important role in attention/vigilance, cognitive functions and behavioral disorders, particularly depression. Results described here show that in the rat, intraperitoneal (i.p.) injection of lipopolysaccharide (LPS, a bacterial endotoxin) causes long-lasting changes in electrophysiological activity of LC neurons that are mediated by interleukin-1 (IL-1) acting locally in the LC region. First, it was found that IL-1, when microinjected into the LC region or stimulated/expressed in that brain region, increased activity of LC neurons. The only exception to this was that a very low dose of microinjected IL-1 (5 pg) decreased LC activity, which could be blocked by an antagonist to corticotropin-releasing hormone (CRH), thus suggesting that the decrease was due to IL-1 stimulation of CRH release. All of these effects could be blocked by injection and/or infusion of IL-1 receptor antagonist (IL-1RA) specifically into the LC region. Next, intraperitoneal (i.p.) injection of a low dose of LPS(10 µg/kg or 100 ng/kg) was also found to increase LC activity. The excitation of LC produced by 10 µg/kg i.p. LPS increased progressively for at least 1 week, with LC neurons firing at more than twice their normal rate at 1 week after the i.p. LPS injection. Alteration of LC activity lasted for 3 weeks after a single i.p. injection of 10 µg/kg LPS. The effects of i.p. LPS on LC activity at any time after i.p. injection could be blocked by a brief microinfusion of IL-1RA into the LC region, thereby indicating that changes in LC activity seen after the i.p. LPS were caused by IL-1 acting in the LC region. Finally, i.p. injection of peptidoglycan, representing gram-positive bacteria, and polyinsinic-polycytidylic acid [poly(I):(C)], representing viral infection, also caused increases in LC activity, and the effects of peptidoglycan [but not those of poly(I):(C)] were blocked by microinfusion of IL-1RA into LC. These findings suggest that bacterial infections can give rise to prolonged changes in brain activity through cytokine action in brain.

In addition to their role as signaling molecules of the immune system, cytokines may participate in central neurotransmission. Variations of the central and/or peripheral levels of the proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-β (IL-1β), impact on neuroendocrine processes as well as central neurotransmitter activity. To a considerable extent, these effects are reminiscent of those elicited by psychogenic stressors. The current review describes recent findings consistent with a role for these cytokines in the neurochemical and behavioral manifestations of clinical depression, as well as the cellular death associated with cerebral ischemia. Moreover, the increasing use of cytokines in the immunotherapeutic treatment of various autoimmune diseases (e.g. rheumatoid arthritis) and cancers prompted us to consider the potential role of central processes in subserving the mood-related side-effects elicited by these treatments. Finally, a single administration of TNF-α has been shown to elicit a time-dependent sensitization effect, wherein the behavioral and neurochemical responses elicited by later cytokine treatment are greatly enhanced. Thus, particular attention was devoted to the possibility that elevated levels of TNF-α, through either exogenous (e.g. immunotherapy) or endogenous (e.g. brain damage or stressors) means may sensitize neurotransmitter or second messenger pathways important for the pathology. Given the time-dependent nature of cytokine sensitization effects, the schedule of cytokine administration during immunotherapy, or the timing of cytokine up-regulation in response to traumatic or stressful events may favor the development of sensitized central processes, which may influence clinical outcome.

Significant evidence suggests that the immune system is capable of profoundly affecting central nervous system (CNS) functioning in ways that may contribute to the development and expression of neuropsychiatric disorders, including disorders of mood. This paper reviews evidence that the production of proinflammatory cytokines, whether in the context of therapeutic administration (e.g. interferon-α-2b for hepatitis C infection) or medical illness, induces a state of sickness behavior that closely resembles major depression. Antidepressants have been shown to abolish or attenuate cytokine-induced sickness behavior in laboratory animals and to protect against the development of major depression in the context of therapeutic cytokine administration in humans. Potential mechanisms by which antidepressants ameliorate depressive and/or sickness symptoms in the context of immune activation include direct effects on immune cell functioning, as well as modulatory effects on monoamine neurotransmitters, intracellular second messenger pathways and the neuroendocrine system, in particular the hypothalamic–pituitary–adrenal axis.