IMMUNOLOGY IN BEHAVIOUR DISORDERS

Role Cytokines in the Brain Activity and Implications for Behaviour Disorders

Dr Widodo Judarwanto SpA, Children Allergy Center, Bunda Hospital Jakarta

Cytokines

• The cytokines are a diverse group of proteins that may be regarded as the hormones of the immune system. These small molecules can be secreted by various cells and act as signals between cells to regulate the immune response to injury and infection. They may be considered to be hormones because their properties are similar to those of the classic hormones of the endocrine system. Cytokines are frequently regulated in cascades, where induction of the early cytokines serves to increase the production of later cytokines (e.g., interleukin-1 [IL-1] stimulates the release of IL-2, IL-6, and tumor necrosis factor [TNF]). The specificity of the response to cytokines is provided by unique cytokine receptors. Cells that express a functional receptor for a cytokine will respond to the presence of that cytokine. These interactions of cytokines and cytokine receptors are a necessary component of the physiologic response to cytokines. Cytokine receptors can also be found in a soluble form. Usually, a soluble receptor for a specific cytokine can inhibit the biological activity of the cytokine by inhibiting the binding of the cytokine to its membrane-anchored receptor (For example, soluble TNF receptors decrease the biological activity of TNF by inhibiting the binding of TNF to its specific surface receptor.) In some instances, the binding of the cytokine to its soluble receptor can form a complex that enhances the biological activity of the cytokine. This rare situation is seen, for example, when IL-6 binds to soluble IL-6 receptors, forming a biologically active complex that adds to the activity of IL-6.
• The study of the genetic basis of disease is a rapidly growing science. Because cytokines play a central role in the pathophysiology of various medical illnesses, genetic polymorphism of specific cytokines and their association with specific disease entities have been widely investigated. Much of the work has centered on TNF- , although other cytokines have also been studied. Polymorphism in TNF genes has been associated with several illnesses, including multiple sclerosis, asthma, myasthenia gravis, and septic shock. No association has yet been reported between cytokine polymorphism and psychiatric illness. The association with septic shock, however, presents interesting theoretical ramifications for psychiatry. Although septic shock is undeniably caused by identifiable bacterial pathogens (environmental factors), genetic polymorphism at the TNF- locus, and in particular the presence of the TNF-2 allele, increases the host’s risk of developing septic shock and the chance of mortality associated with it. This model of gene-environment interaction may be of relevance to psychiatry. Genetic polymorphism at a yet unidentified locus or loci relevant to a specific psychiatric illness may have profound implications for the risk of developing the illness in the face of varying environmental stressors. Polymorphism within the promoter of the serotonin transporter gene, for instance, has been associated with a differential response to specific antidepressant medications .
• The nomenclature of the cytokines can be confusing, primarily because they are frequently named for their biological activity. The names of some of the early identified cytokines have become so ingrained in the literature that these names will probably not change despite attempts to standardize the nomenclature. Referring to the cytokines by their activity lacks specificity because cytokines are pleotropic and are involved in multiple biological activities. It is possible for two groups of investigators to be working on the same molecule, but to be focusing on different aspects of its functional capacity. Attempts at standardization have therefore included assigning interleukin numbers to cytokines as their genes are sequenced. This method has not been uniformly applied to all newly discovered cytokines, partly because many members of supergene families are often discovered. For example, IL-8 was initially described, and subsequently multiple additional members of this family have been cloned. This group of molecules associated with IL-8 are called chemokines.
  

Cytokines and Neuroimmunology

• The brain has for many years been considered an immunologically privileged site, suggesting reduced or altered immunological responsivity. Evidence in this regard includes the brain’s lack of adequate lymphatic systems to capture antigens, protection from circulating blood by the blood-brain barrier, and failure to exhibit a "classic inflammatory response" characterized by early invasion of macrophages and leukocytes. Recent developments in neuroimmunology however have challenged some of these concepts.
  The brain can certainly exhibit many of the hallmarks of inflammation in response to infection or injury. They include edema, activation of resident phagocytes (microglia), local invasion of circulating immune cells, and production of cytokines. The role of these various cytokines in different brain activities is a topic of intense investigation and debate at the present time.

Cytokine Localization in the Brain

• Before we discuss any role for cytokines in brain activity, we need to address the issue of the sources of brain cytokines, because cytokines as such cannot cross the blood-brain barrier, at least under physiologic conditions. How then do cytokines communicate with brain cells? Four mechanisms for brain signaling by cytokines have been postulated : passive transport of cytokines into the brain at circumventricular sites lacking a blood-brain barrier; 2) binding of cytokines to cerebral vascular endothelium, thereby inducing the generation of secondary messengers such as prostaglandins and nitric oxide; 3) carrier-mediated transport of cytokines into the brain, across the blood-brain barrier; and 4) activation by cytokines of peripheral afferent nerve terminals at the site where cytokines are released. These mechanisms are not mutually exclusive. They depend in part on the location of the inflammatory stimulus and the disease state of the organism.
  But cytokines do not always have to reach the brain, either directly or indirectly, from the periphery to be able to play a role in brain activity. Most cytokines can be synthesized and released within the central nervous system. Although most cytokines in the brain are secreted by astrocytes and/or microglia, some evidence suggests that under certain conditions, neurons can also produce cytokines. Furthermore, although cytokines are usually secreted in response to specific stimuli such as infection or injury, there is evidence that low-level expression of specific cytokines is constitutive in blood vessels within the brain. Cytokines in the brain are also regulated in cascades, with evidence of feedback loops, both positive and negative, at different levels. As for the localization of cytokine pathways within the brain, IL-1 has been found in several brain regions, including the hippocampus and specific hypothalamic structures such as the paraventricular nucleus and the arcuate nucleus. IL-1 immunoreactive nerve fibers have also been described in the human brain, particularly in the hypothalamus. Widespread TNF and other cytokine immunoreactivity has been detected in the murine brain. Cytokine receptors have also been detected in several areas of the brain . The precise mapping of various cytokine pathways and their receptors in the brain, however, remains incomplete.
  

Cytokines and Associated Brain Activities

• Once in the brain, cytokines have been associated with various brain activities. These include immunologic, neurochemical, neuroendocrine, and behavioral activities. Here again, the bulk of the experimental evidence centers on IL-1. Selected effects of IL-1 in the brain, as well as elsewhere in the body. For a more complete presentation of IL-1 effects, several reviews are available.
• Behavioral effects : Although part of the response of the organism to an infection or injury is local and occurs at the cellular and molecular levels, another part is more general, occurs at the level of the entire organism, and involves specific adaptive behaviors. These effects can also be seen as part of the overall mechanism to maintain homeostasis. We know now that several of the behaviors associated with infection, such as increased sleep, decreased appetite, and decreased sexual drive, which are often referred to as "sickness behavior," may be at least partly attributed to the specific effects of cytokines. These behaviors can be "adaptive" during the course of an acute infection or trauma, allowing the organism to mobilize all necessary resources to the task of healing itself.
• Although it is well recognized that infection is commonly associated with somnolence and fatigue, the mechanism of such behaviors has only been investigated within the last 10 years. It is now believed, for instance, that muramyl peptide, a common microbial product, and endotoxin stimulate the release of IL-1 and that IL-1 interacts with specific neurohormones and neurotransmitters in the brain to produce somnogenic activity. Additional evidence suggests that plasma levels of IL-1 peak at the onset of slow-wave sleep in healthy human volunteers and levels of IL-1 in cerebrospinal fluid increase during sleep. Specific cytokines therefore seem to play a role in sleep regulation, particularly during an infection. Although most research in this area has focused on IL-1, there is growing evidence that TNF- and interferon may also have somnogenic activities, while IL-2, IL-6 and TNF-b probably do not. Sleep regulation is a complex phenomenon and involves interactions between neuropeptides, biogenic amines, and other neurotransmitters.
• The exact role played by specific cytokines remains to be determined.
  Another commonly observed behavior during infection and cancer is diminished appetite or anorexia. Plata-Salaman and colleagues studied the effects of chronic intracerebroventricular microinfusion of various cytokines on feeding and drinking behaviors in rats. They found that IL-1b decreased nighttime feeding in these animals in a dose-dependent manner. This effect was abolished if IL-1b was heat-inactivated or was given along with IL-1 receptor antagonist. Water intake was not affected in this paradigm. TNF- and IL-8 were less effective than IL-1b in producing these changes. IL-2, IL-4, and IL-10 had no such effects. In human studies, treatment with cytokines is often accompanied by nausea and anorexia as common adverse effects. Furthermore, there is evidence that patients with anorexia nervosa, despite a decreased capacity to produce IL-2, have in their sera one or more factors that stimulate the production of cytokines.
• Immunologic effects : Consistent with its activities in other organs, IL-1 in the brain stimulates the production of other cytokines by specialized cells, in this case astrocytes and microglia. Human astroglial cell lines stimulated by IL-1 have been shown to produce colony-stimulating factor, TNF- , additional IL-1, and IL-6. There is also evidence that intracerebroventricular injections of IL-1b in rats are associated with a decrease in natural killer (NK) cell activity of circulating lymphocytes and the release of IL-6 into the blood stream. IL-1 directly injected into the brain can also stimulate astrogliosis and produce neovascularization.
• Neurochemical effects : A number of studies suggest that specific neurochemical changes occur in the brain of animals in response to an immunological challenge. The same effects could also be obtained with systemic injection of cytokines. Dunn and Wang have shown that intraperitoneal injections of IL-1b to mice were accompanied an hour later by increases in brain concentrations of 3-methoxy;4-hydroxyphenylethyleneglycol (MHPG) (mostly in the hypothalamus), 5-hydroxyindoleacetic acid (5-HIAA) (in different parts of the brain), and much smaller increases in 3,4-dihydroxyphenylacetic acid (DOPAC). Similar results have been reported for IL-2 and to some extent IL-6. TNF and interferon, however, do not seem to produce such effects.
• Neuroendocrine effects : Although it has been known for many years that infection is often accompanied by an increase in hypothalamic-pituitary-adrenal (HPA) activity, the exact mechanism has only been elucidated in the last 15 years. Besedovsky and colleagues first reported that the immune response to an injection of sheep red blood cells into rats was accompanied by increases in plasma levels of corticosterone. Several investigators later reported that administration of IL-1 was associated with increases in corticotropin-releasing hormone, ACTH, and corticosteroids. There is also evidence that IL-6, TNF, and interferon are capable of stimulating the HPA axis both in rodents and in man . The results are equivocal for IL-2. Regardless of the mechanism involved, HPA actition and the resultant hypercortisolemia frequently act as a negative feedback mechanism to suppress an otherwise exaggerated immune/inflammatory response initiated by the chain of cytokines . This delicate balance seems to be part of a homeostatic mechanism, the failure of which could result in serious disorders such as infection, cancer, or autoimmune disease. Because the brain plays a central role in this feedback loop, factors such as emotions and/or psychosocial stressors can tilt the balance one way or the other. There is also evidence that cytokines can modulate the hypothalamic-pituitary-thyroid axis and the hypothalamic-pituitary-gonadal axis .
  

Cytokines and Behaviour Disorders

• Because cytokines are closely associated with central neurotransmitters and because cytokine regulation is affected by stress, a number of studies have investigated a possible role for cytokines in behaviour disorders. These studies have been described in an emerging literature on cytokine regulation in major depression, schizophrenia, Alzheimer’s disease, and other psychiatric disorders.
• The literature includes reports of cytokine dysregulation in other behaviour disorders, such as sleep disorders, ADHD, ADD, panic disorder, obsessive-compulsive disorder, and autism.
  

End Points

• More hypothesis-driven research protocols involving human subjects are needed to assess the role of specific cytokines in neuroimmunology symptom production as well as their role in the pathophysiology of specific behaviour disorders.
• The last decade has witnessed a rapid expansion of research in cytokine biology. In addition to their role as messengers among inflammatory and immune cells, these proteins seem to interact with different tissues and organs and assume new roles outside their traditionally known functions. One such role involves the central nervous system.
• Cytokines seem capable of acting as neuromodulators within the brain. As such, they affect important brain activities such as sleep, appetite, and neuroendocrine regulation.
  Discoveries about these processes have led to speculations about a possible link between cytokines and psychopathology. We should, however, emphasize that our knowledge of the role of cytokines in human brain activity is still in its infancy. Most of our information comes from animal studies. Human studies remain scarce and frequently suffer from methodological flaws that make comparisons between the results difficult to achieve.
  

REFERENCES

• Plotnikoff N, Murgo A, Faith R, Good R (eds): Cytokines: Stress and Immunity. Boca Raton, Fla, CRC Press, 1999
  Rothwell NJ (ed): Cytokine in the Nervous System. Georgetown, Tex, PG Landes, 1996
  Ransohoff RM, Benveniste EN (eds): Cytokines and the CNS. Boca Raton, Fla, CRC Press, 1996
  Licinio L, Kling M, Hauser P: Cytokines and brain function: relevance of interferon a-induced mood and cognitive changes. Semin Oncol 1998; 25:30–38
  Konishi Y, Chui DH, Kunishita T, Yamemura T, Higashi Y, Tabira T: Demonstration of interleukin-3 receptor-associated antigen on the central nervous system. J Neurosci Res 1995; 41:572–582
  Wong ML, Bongiorno PB, Rettori V, McCann SM, Licinio J: Interleukin-1 beta, interleukin-1 receptor antagonist, IL-10 and IL-13 gene expression in the central nervous system and anterior pituitary during systemic inflammation: pathophysiological implications. Proc Natl Acad Sci USA 1997; 94:227–232
  Thompson A (ed): The Cytokine Handbook, 3rd ed. San Diego, Academic Press, 1998 Mosmann TR, Coffman RL: TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 1989; 7:145–173
  Besedovsky H, Sorkin E, Keller M, Müller J: Changes in blood hormone levels during the immune response. Proc Soc Exp Biol Med 1975; 150:466–470
  Nakano Y, Nakamura S, Hirata M, Harada K, Ando K, Tabuchi T, Matunaga I, Oda H: Immune function and lifestyle of taxi drivers in Japan. Ind Health 1998; 36:32–39
  Watkins LR, Maier SF, Goehler LE: Cytokine-to-brain communication: a review and analysis of alternative mechanisms. Life Sci 1995; 57:1011–1026
  Freidin M, Bennett MVL, Kessler JA: Cultured sympathetic neurons synthesize and release the cytokine interleukin-1b. Proc Natl Acad Sci USA 1992; 89:10440–10443
  Maes M, Bosmans E, Meltzer HY, Scharpé S, Suy E: Interleukin-1b: a putative mediator of HPA axis hyperactivity in major depression? Am J Psychiatry 1993; 150:1189– 1193
  Brambilla F, Bellodi L, Perna G, Bertani A, Panerai A, Sacerdote P: Plasma interleukin-1b concentrations in panic disorder. Psychiatry Res 1994; 54:135–142
  Brambilla F, Perna G, Bellodi L, Arancio C, Bertani A, Perini G, Carraro C, Gava F: Plasma interleukin-1b and tumor necrosis factor concentrations in obsessive-compulsive disorders. Biol Psychiatry 1997; 42:976–981
  Rogler G, Andus T: Cytokines in inflammatory bowel disease. World J Surg 1998; 22:382–389 Sapolsky R, Rivier C, Yamamoto G, Plotsky P, Vale WW: Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor. Science 1987; 238:522– 524
  Bernton EW, Beach JE, Holaday JW, Smallridge RC, Fein HGZ: Release of multiple hormones by a direct action of interleukin-1 on pituitary cells. Science 1987; 238:519–521
  Rivier C: Neuroendocrine effects of cytokines in the rat. Rev Neurosci 1993; 4:223–237
  Moldofsky H, Lue FA, Eisen J, Keystone E, Gorczynski RM: The relationship of interleukin-1 and immune functions to sleep in humans. Psychosom Med 1986; 48:309–318
  Lue FA, Bail M, Jephthah-Ochola J, Carayanniotis K, Gorczynski R, Moldofsky H: Sleep and cerebrospinal fluid interleukin-1-like activity in the cat. Int J Neurosci 1988; 42:179–183
  Plata-Salaman CR, Sonti G, Borkoski JP, Wilson CD: Anorexia induced by chronic central administration of cytokines at estimated pathophysiological concentrations. Physiol Behav 1996; 60:867–875