the neuroimmunological basis of behavior and mental disorders || molecular basis of cytokine...

59A. Siegel, S.S. Zalcman (eds.), The Neuroimmunological Basis of Behavior and Mental Disorders, DOI 10.1007/978-0-387-84851-8_4, © Springer Science+Business Media, LLC 2009

Molecular Basis of Cytokine Function

Pranela Rameshwar and Arlene Bardaguez

Abstract Cytokines are soluble glycoproteins that are ubiquitously produced by immune and other cells. The family of cytokines also includes a subset of small molecules, designated. Although the cytokine receptors share some subunits, they show specificity for binding and signaling. Unlike hormones that act at sites distant from the area of production, most cytokines are easily degraded. Thus, in general, cytokines mediate functions via autocrine and paracrine manner. However, cytok-ines can initiate functional responses at low concentrations, which could cause sub-tle brain effects. In contrast, cytokines have also been given attention in medicine through the `cytokine storm,’ which result in general illness. Cytokine storm could arrive from bacterial and viral infections. The chapter discusses the molecular basis for behavioral dysregulation that could result from cytokine production.

Key words Cytokines · Immune system · Interleukins · Chemokines

1 Introduction

The general term for molecules belonging to chemokine, interleukin, and lym-phokine families. Cytokines are soluble glycoproteins produced by several cells, but a designation of cytokine requires production by immune cells. Cytokines do not require enzymatic processing for signaling, but binds to specific receptors present on immune and neural cells, among others. In contrast to hormones that act at sites distant from the area where they are produced, most cytokines are easily degraded. The similarity between cytokines and hormones is limited to their efficacy at low levels, and high affinity binding to specific receptors. Because of their effects at low concentrations, their levels just above baseline can initiate multiple anatomical pathophysiological conditions. The recognized effects of cytokine in medicine have led to the concept of cytokine storm (Clark, 2007). This term generally refers to the

P. Rameshwar ( )Departments of Medicine, UMDNJ–New Jersey Medical School, Newark, NJ, USAe-mail: [email protected]

60 P. Rameshwar and A. Bardaguez

unpleasant feeling caused by increased cytokine production following infection with the influenza virus. However, similar mechanisms are attributed to other infections, which could lead to secondary effects on other organs, including brain functions.

A review on cytokines is not completed unless credit is given to its discovery. An acknowledgment should be given to the work by Dr. Stanley Cohen and colleagues whose original designation, cytokines, has not deviated much from the current descrip-tion of the growing number of cytokines (Cohen, 2004, 1986; Antonia et al., 1986).

Cytokines are subdivided into four different classes, based on their structure. The family with four alpha-helix bundles is further subdivided into interleukin (IL)-2, interferon, and IL-10 subfamilies. The other three families are grouped as IL-1, IL-17, and chemokine. The structural discrimination is important since functional redundancy is a hallmark of cytokines. In each category or subcategory, the total numbers are continually updated with the identification of new members (Uze and Monneron, 2007).

2 Interleukins

The interleukins, which currently include >30 members belong to the family of cytokines (Weinreich et al., 2006). Since the interleukins are a subgroup of cytok-ines, they are subjected to the rules of designation as a family of glycoproteins. The

Fig 1. Cytokines are shown as central to the interactions between the brain and the immune system. Infection or psychosocial stress can change cytokine levels. In the case of pregnancy, both the mother and child can be affected.

Cytokines

Immune System

Brain

Psychosocial Stress

BEHAVIORAL CHANGES

Molecular Basis of Cytokine Function 61

interleukins are produced by immune and other cells with varying, but redundant functions. The term interleukin was originally named because upon their discovery, it was believed that their production from immune cells resulted in communica-tion with other immune cells. Since the immune cells were presumed to be leuko-cytes or white blood cells, this explains the term interleukin, which means between leukocytes.

At the early periods of discovery, the term interleukin was limited to molecules that targets white blood cells. In recent years, the number of interleukins is rapidly expanding with the current number up to 33 (Iikura et al., 2007). The stringent designation of the term interleukin to effects on leukocytes has become difficult to follow and therefore makes it difficult to define them within a narrow range of functions.

Attempts have been made among international scientists for a consensus to apply the term interleukin (WHO-IUIS, 1992, 1997). Results of multiple international meetings led to four criteria when deciding on the designation of interleukin. Firstly, the gene and amino acid sequences should be iden-tified and also demonstrated in molecular studies to be expressed as secreted proteins. The sequence cannot be from another gene that has already been cloned with a different designation. Secondly, the molecule has to be shown to be endogenously produced by cells of the immune system and should exhibit multiple functions. Thirdly, despite the previous criteria if the gene was previ-ously cloned and its major functions belong to tissues and/or organs other than those within the immune system, the molecule should retain its original name rather than adding to the list of interleukins. Fourthly, the discoverer is left to opt for a descriptive name rather than an interleukin. Scientists have tried to adhere to the four criteria but the difficulty arises when they are faced with the fourth. IL-24 is a typical example of an interleukin that was originally cloned in melanoma cells and has been found to impart anti-cancer effects (Chada et al., 2004). Subsequently, IL-24 was discovered to function as a cytokine and share intracellular signaling similar to several other cytokines such as those belonging to the IL-10 family (Chada et al., 2004). Since IL-24 has been shown to exhibit a potent anti-cancer effect, scientists have designated this molecule as an interleukin and also as its original name, melanoma differentiation associated gene (MDA) in combination with IL-24. Thus it is common for this gene to be designated IL-24.MDA (Oida et al., 2007; Chen et al., 2005; Fisher 2005). IL-22 represents an example that show dual roles, as an immune modulator, and in other organs (Levillayer et al., 2007; Oral et al., 2006; Zheng et al., 2007).

The IL-10 family of cytokines includes several members including IL-10, IL-22, IL-24, IL-26, IL-28, and IL-29 (Sabat et al., 2007; Kotenko and Langer, 2004). The complexity in the functions of this family of cytokines is compounded by several members sharing receptor subunits and even cross react with the receptor of each other (Kotenko and Langer, 2004). Another confounds in this large IL-10 family of cytokines is that some members (IL-19 and IL-20), although they are produced by immune cells, it is unclear if they regulate immune functions (Sabat et al., 2007). Ongoing in vivo studies on disease model suggest that the IL-10 family


of cytokines might be involved in the inflammatory cascade, either as anti- and/or pro-inflammatory mediators (Sabat et al., 2007).

3 Chemokines

The chemokine group comprises a large family of small cytokines of approximately 8–10 kDa (Murphy et al., 2000). Since the chemokines belong to a subgroup of cytokines, their designations follow those linked to cytokines, as outlined above. The designation of chemokines under a separate category is mainly due to their properties in attracting immune cells to each other or to an organ of inflamma-tion (Ruffini et al., 2007). Immune or other cells that express chemokine recep-tors tend to migrate towards regions of high chemokine levels, such as regions of tissue injuries. Besides the chemoattractant property, the chemokines are grouped together based on their 3D structures. Initially, the same chemokine was referred to by multiple names. This problem has been corrected after the international union of nomenclature agreed on consensus names for each member of the family (Murphy et al., 2000).

There are four cysteine residues found within conserved regions of the chemokines, which are important for their 3D structures (Fernandez and Lolis, 2002). The first two cysteines are towards the N-terminal end of the protein; the third at the centre and the fourth towards the C-terminal (Fernandez and Lolis, 2002). The first and third cyteines are connected by disulphide bonds, and the second to fourth residues are similarly connected. The 3D structures resulted in several loops (Fernandez and Lolis, 2002). The size of the loop formed between the first two cysteines, which depends on the spacing forms the N-loop. The chemokines are grouped into four categories, based on the spacing between the two cysteines: CC or β-chemokine, CXC or α-chemokine, C or γ chemokine, and CX

3C or δ-chemokines (Fernandez and Lolis, 2002). The CC chemokines

comprise more than 20 members (Laing and Secombes, 2004a, b). The CXC chemokines comprise approximately 17 members (Laing and Secombes, 2004a, b). Unlike the other chemokines, the C type has only two cysteines and has few members, of which there are XCL1 and XCL2 (Laing and Secombes, 2004a, b). The fourth group, CX

3C, has only one member with three amino acids between the

two cysteines, CX3CL1 (Laing and Secombes, 2004a, b).

Chemokines are considered to exhibit mostly pro-inflammatory properties. They are produced during an immune response for the purpose of attracting additional immune cells to the site of infection (Mantovani et al., 2006). In contrast to their inducibility during infection, other members of this family, including SDF-1α/CXCL12, could be involved in homeostasis in an organ-specific method (Majka and Ratajczak, 2006). Specifically, CXCL12 is constitutively produced by bone marrow stromal cells for the purpose of retaining the hematopoietic stem cells in the region. This occurs by interactions between membrane-bound CXCL12 pres-ent on stromal cells and the receptor (CXCR4)-expressing stem cells (Majka and


Ratajczak, 2006). CXCL12 continues to maintain the movement of hematopoeitic stem cells within bone marrow through a gradient changes in its levels across bone marrow.

4 Colony Stimulating Factor (CSF) and Tumor Necrosis Factor (TNF)

These categories of cytokines require a separate subheading because of their crit-ical roles in immune responses, but are not grouped within the interleukins and chemokine members. The CSF family is neglected when considerations are placed in behavioral and other pathophysiology caused by cytokines. The CSFs are mostly thought as growth factors mainly due to their roles as hematopoietic stimulators (Touw and van de Geijin, 2007). The three CSFs are granulocyte-colony stimulat-ing factor (G-CSF), macrophage-colony stimulating factor (M-CSF), and granulo-cyte–macrophage-colony stimulating factor (GM-CSF). G-CSF and GM-CSF are commonly used in patients for neutropenia and in the case of G-CSF, for mobilizing hematopoietic stem cells from donor bone marrow for the purpose of transplanta-tion in an allogeneic donor (Kuderer et al., 2007, Winkler and Levesque, 2006).

TNF are found in two forms, the α- (cachetin) and β- (lymphotoxin) forms and share the types 1 (TNF-R1) and 2 (TNF-R2) receptors (Locksley et al., 2001). TNF-R1 is ubiquitously expressed whereas TNF-R2 is only on immune cells (Locksley et al., 2001). As compared to studies on TNF-R1, there is limited information on the type 2 receptor. TNF induces trimerization of the receptors, which caused conformational change and activation of the receptor. The activa-tion follows the disassociation of SODD, which suppresses the intracellular death domain. In exchange, the death domain comes in contact with the adaptor pro-tein TRADD (Wajant et al., 2003; Chen and Goeddel, 2002). TRADD acts as an adaptor protein for other activators, which resulted in multiple intracellular path-ways (Wajant et al., 2003; Chen and Goeddel, 2002). The pathways include NFκB activation, which is involved in varying inflammatory responses and the induc-tion of anti-apoptotic mediators. In contrast to the pro-inflammatory properties by NFκB activation, TNF can activate MAPK pathways that are involved in cell differentiation, proliferation, and the activation of pro-apoptotic factors. TNF also could induce cell death, although this property is less prominent as compared to other TNF family members linked to cell death (Gaur and Aggarwal, 2003). The weak apoptotic property of TNF, combined with the pro-inflammatory property of NFκB brings up a critical point of balances between these two functions following exposures to TNF.

The properties of TNF overlaps with those of IL-1 with respect to the induction of systemic inflammation, in particular fever. Also, TNF increase the metabolism of muscle and cause loss of fat in adipocytes, which lead to cachexia. TNF has been linked to septic shock. Despite these links, trials with TNF antagonists have not shown much promise (Inanc and Direskeneli, 2006).


5 Cytokine Receptors

An understanding of cytokine receptors regardless of their secondary or tertiary structures has significance to experimental research and also to the development of therapeutic targets. Regardless of the classifications, this does not eliminate the fact that cytokines show functional pleotrophism. The cytokine receptors are clas-sified as type 1 immunoglobulin (Ig) superfamily, type 2 interferon family, type 3 tumor necrosis factor family and those belonging to the G-protein family receptors (Zlotnik et al., 2006; Krause and Pestka, 2005; Boulay et al., 2003). The type 1 family of receptors is ubiquitously expressed and includes receptors for IL-1 and IL-2. The type 1 receptors also include those that interact with CSFs with con-served motifs in their extracellular regions. The type 2 receptors bind to the inter-feron family of cytokines (Zlotnik et al., 2006; Alves et al., 2007; Boraschi and Tagliabue 2006; Murphy and Young, 2006). The type 3 TNF family comprises receptors with cysteine-rich extracellular binding domains (Alves et al., 2007). The 7-transmembrane G-protein coupled receptors are limited to members of the chemokines (Zlotnik et al., 2006).

6 Cytokines in the Nervous System

The nervous and immune systems are connected anatomically by nerve fibers and by other functions such as the migration of cells into the brain as well as the movement of soluble factors into and out of the brain (Quan and Banks, 2007). The immune system includes the secondary and primary lymphoid organs of which the latter include the thymus and brain. The transport of cytokines across the blood–brain barrier has evolved from the concept where there was demar-cation between normal and diseased brain to current information on the move-ment of cytokines via secretion of cytokines or via transporters (Quan and Banks, 2007). These series of findings have led to an understanding of the mechanisms by which cytokines are central to the peripheral diseases and brain and vice versa (Banks, 2006a).

The brain and its peripheral connections are targets of drug delivery (Banks, 2006b). During testing of drug delivery, the pharmacological dose might be dif-ferent between homeostasis and in cases where cytokine levels are increased or decreased in the brain and/or peripheral organs. Thus, an understanding of the types and levels of cytokines in the brain would lead to higher efficacy in drug deliveries. During drug testing, the levels and types of cytokines are not the only consideration. Cytokines can affect neuronal functions, which might affect the efficacy of a drug (Viviani et al., 2007).

The presence of cytokines in brain could also be from endogenous sources. Microglia, which are considered as brain macrophages could produce cytokines in response to various brain insults (Kriz, 2006; Wang and Suzuki, 2007). Micro-glia has been reported to mediate neuroprotective functions, following acute brain


injury (Simard and Rivest, 2007). Since microglial cells are sources of cytokines, the question is when these cells become protective and when they are harmful. These are relevant questions that will require robust experimental analyses at the single cell level and by electrophysiology to determine how cytokines could function as mediators of microglial effects.

In contrast to the pathogenic effects of cytokines in the brain, the interferons can also dampen the inflammatory responses in the brain such as in multiple sclerosis (Bagnato et al., 2007). An interesting role for cytokines is the effects of IL-1 on the regulation of brain volume (Oprica et al., 2007). This role is important since it might be relevant to an understanding of aging disorders associated with the central nervous system.

7 Cytokines and Neuroprotection

This section discusses the potential of cytokines for neural protection. While the experimental studies might show neural protection, genetic variation among indi-viduals is an important point that could affect the effects of a particular cytokine in brain function (Wilson and Montgomery, 2007). Besides genetic variation, the complexity on cytokine functions is compounded by the influence of several other genes and polymorphism. Although erythropoietin (Epo) is not a cytokine, its action has been incorporated within networks of cytokines. This type of network has been studied extensively in bone marrow functions (Fliser and Haller, 2007). Epo has been shown experimentally to mediate neuroprotection and to direct cell fate toward neurogenesis while suppressing gliogenesis in neonatal stroke (Gonzalez et al., 2007).

Stem cell therapy has been proposed as a viable form of therapy for brain repair (Takahashi, 2007). Since cytokines are produced by the stem cells and endogenous cells, the microenvironment that is established by the implanted stem cells will influ-ence the outcome by stem cells. The imperative questions will surround the types and levels of cytokine production, their receptor expression, the developmental changes in cytokines and the effects on the brain.

The protective roles of cytokines could be hindered in cases of brain tumors, which could produce cytokines that facilitate the survival of the tumor cells rather than to affect brain functions (Zisakis et al., 2007). While brain tumors exhibit acute production of cytokines, depression and dementia show chronic produc-tion of cytokines (Leonard, 2007). The chronic production of cytokines remain an unresolved issue since it is unclear if this is secondary to other underlying disorders or if this could be involved in the pathophysiology of dementia and depression. A role for cytokines in depression has been demonstrated in experi-mental studies in which a nonsteroidal anti-inflammatory agent, COX2 inhibitor, reversed the behavioral pattern of a rat model of depression (Myint et al., 2007). Another evidence for the effects of cytokines on depression is the role of lipopoly-saccharide, which is a pro-inflammatory agent, as a depressogenic agent (Pekary et al., 2007).


8 Cytokines in Vasculogenesis: Relevance to Brain Functions

This section discusses the possibility of taking advantages of cytokines in enhanc-ing vasculogenesis by attracting endogenous endothelial progenitors. In some cases, excess blood vessels could be undesirable since they support the pathophys-iology of the disease such as cancer. In other cases, rapid increase in vasculogen-esis could be a positive treatment option. Of particular relevance are disorders of the brain in which lack of blood supplies lead to brain damage. The concept proposed for enhanced vasculogenesis for wound healing can be extrapolated to brain disorders (Velazquez, 2007). At present, the research is focused on attract-ing endothelial progenitors from the bone marrow to the region of injuries. This source of progenitors might be delayed if rapid attraction is required in the brain. In this regard, it might be prudent to begin studies to determine how neural stem cells could be challenged to form endothelial cells and to identify which cytokines could be involved in the process. This area of investigations could lead to future therapies. Since chemokines are the prototypical chemoattractants, and they are commercially available, an injection at the site of injury could be another method to attract bone marrow-derived cells for the purpose of increasing vasculogenesis (Shireman, 2007).

9 Cytokines in Pregnancy and Behavior

Genetic causes have been the focus for mental disorders. However, in several of these studies, there is evidence that non-genetic factors might be responsible for the disease (Patterson, 2007). While most of these non-genetic causes have been asso-ciated with the environment, other endogenous changes could also be involved in behavioral changes. The changes observed during pregnancy represent prototypical cases where cytokines have been linked not only to brain functions of the mother, but to brain development of the fetus.

During infection endotoxin could enhance dopamine release, which could result in behavioral changes in the mom and possible developmental defects in the neo-nate’s brain (Romero et al., 2006). Since endotoxin is a potent inducer of cytok-ines, this type of pathophysiology could be treated if the causative cytokines and the mechanisms are understood. The fact that neurons express cytokine receptors indicate that their roles as mediators by endotoxin produced during bacterial infec-tion (Greco and Rameshwar, 2007). Animal models in which the neonates have been exposed to IL-2 showed neurobehavioral problems linked to autism (Ponzio et al., 2007). The autistic behavior of the fetus during pregnancy is not limited to IL-2. Animal studies in which IL-6 was knockout implicated this cytokine as a factor involved in predisposing the fetus to schizophrenia and autism (Smith et al., 2007).

Psychosocial stress during late stage pregnancy could lead to the production of cytokines (Coussons-Read et al., 2007). The production of cytokines during this


period of pregnancy can affect the outcome such as preeclampsia and premature labor (Coussons-Read et al., 2007). In addition to the risk to pregnancy, there could be long-term risk to the fetus, based on animal models (Vanbesien-Mailliot et al., 2007).

10 Conclusion

Decades of research have identified numerous molecules that fall under the cat-egory of cytokines. Several costly clinical trials have been done, yet it has been more than 15 years since the US Food and Drug Administration has approved a new cytokine for hematological disorder (Weinreich et al., 2006). There are effec-tive treatments with cytokines for inflammatory diseases. While TNFα has been a target in inflammation, therapies are needed to suppress inflammation while induc-ing anti-inflammatory mediators such as IL-10 (Tilg et al., 2007). In many cases, the benefit of cytokines appear positive, but this optimism is dampened by toxic-ity, partly caused by behavioral changes (Kalaaji, 2007; Minderhoud et al., 2007; Malone et al., 2007).

The question that lingers is the methods by which cytokines would fit into the general scheme of future therapy? The evolving roles of stem cells as cellular therapy, including neural diseases are of tremendous interest since the interaction between the stem cells and the diseased microenvironment would be critical to suc-cessful therapy. Since cytokines may have major roles in the cellular communica-tion between a diseased microenvironment and the stem cells, it might be wise to continue to determine the roles of cytokines in stem cell therapy for neural disease, including brain behavior. Small molecules as targets for cytokines could bene-fit with current therapies of silencing RNA to inhibit specific cytokine functions (Svoboda, 2007).

In addition to cytokines and their receptors as potential drug targets, intracellular signaling molecules can also function as drug targets. STAT3, which is activated by various cytokines and is negatively regulated by the suppressor of cytokine sig-naling (SOCS), has been suggested as potential targets for the inflammatory lungs (Gao and Ward, 2007). AKT/PKB, which is activated by several cytokines, were also proposed as potential drug targets for type-2 diabetes and cancer (Manning and Cantley, 2007). Ultimately, we propose that specific targets of cytokines, their receptors, and/or intracellular molecules might be more efficient targets as compared to non-specific anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (Rainsford, 2007). Cytokines are critical to debilitating diseases such as can-cers and are involved in the related fatigue, which also involved central nervous system effects (Ryan et al, 2007). This final point underscores the need for contin-ued dissection of molecular pathways to treat disorders since cytokines in brain will

affect peripheral organs and vice versa.

Acknowledgments This work was supported by the FM Kirby Foundation.


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the neuroimmunological basis of behavior and mental disorders || molecular basis of cytokine...

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