Introduction

Cytokines represent a group of transiently expressed, low molecular weight molecules that fulfill a vital role in intercellular communication, particularly in the immune system. Cytokines regulate numerous physiological and pathological events such as lymphocyte development and activation, programmed cell death, and inflammatory processes. Research over the past decade has lead to the discovery of many new cytokines and their respective cell surface receptors and has elucidated the signaling...

Chemokines And Neuronal Development

Chemokines are classified into four classes based on the positions of key cysteine residues C, CC, CXC, and CX3C and their actions are mediated through high- and low-affinity G-protein-coupled receptors 91,92 . Four of five CXCRs (CXCR2-CXCR5) are expressed in the CNS. Subsets of projection neurons in various regions of the spinal cord and brain express high levels of CXCR2 93 . One CXCR2 ligand, IL-8, is expressed by activated astrocytes, and in vitro studies found it can...

Contents

Innate vs. Immune B. Leukocyte Entry to the C. Chemokines Direct Leukocyte Entry to the D. T-Cell Triggering in the III. The Role of Cytokines in CNS IV. Cytokines That Direct Immune Responses in the CNS 118 A. The Th1 vs. Th2 B. The IL-12 D. Other Potential Th1 Switch 120 F. Type I V. Effector Cytokines As Each Falls, Another Rises to Take A. The TNF B. Lymphotoxins, Light and D. Nitric Oxide and Inducible Nitric Oxide VI. Cytokines in Regeneration and A....

References

Macrophages and microglia in the nervous system, Trends Neurosci. 11, 273, 1988. 2. Dickson D.W., Lee S.C. Microglia. In Textbook of neuropathology 3rd edition (eds. Davis R.L., Robertson D.M.). Williams & Wilkins Baltimore, 165. 1997. Lassman H., Hickey W.F. Dynamics of microglia in brain pathology radiation bone marrow chimeras as a tool to study microglia turnover in normal brain and inflammation, Clin. Neuropathol. 12, 284, 1993. Gehrmann J., Matsumoto Y.,...

The Oligodendrocyte As A Target Of Inflammatory Damage

The analysis of inflammatory damage to oligodendrocytes has mostly been carried out in the context of multiple sclerosis (MS), but it is clear that inflammatory processes damage white matter in multiple other contexts. Causation of white matter damage in MS appears to be quite complex. One component thought to contribute to MS-associated damage is an autoimmune reaction against myelin antigens. In most MS plaques, it is possible to visualize immunoglobulins and deposits of complement at the...

Conclusions

Although we have discussed each cytokine individually relative to their unique roles in potentiating or modulating CNS inflammation, the situation is certainly more complex when considering the dynamic interactions that occur in an inflammatory microenvironment containing multiple cell types producing multiple cytokines. Considering the existing evidence, it would appear that balance between Th1 and Th2 responses and the innate and adaptive immune system is pivotal in controlling inflammation...

F

To date, it remains unclear whether the active configuration of the receptor complex is a tetramer (as described above) or a hexameric complex of two cytokine molecules two a-receptors and two gp130 proteins is the active IL-6 receptor complex 6,15,16 . Also for the IFN cytokine family, an active hexameric receptor complex has been proposed. In the case of IFNy (Figure 3.1E), a complex of two cytokine molecules bound to two a-receptor proteins has been crystallized 17 . But...

Table

Cytokine Actions in CNS Inflammation TNFa, MCP-1 CCL2, TCA-3 CCL1, IP10 CXCL10, CXCL1 KC Groa, CCL21, CCL5 RANTES, CXCL2 MIP2 CXCL1 KC Groa, TNFa IL-12 family, IL-18, IL-10, Type I interferons, osteopontin IFNy (human), TNFa, lymphotoxin, TRAIL, LIGHT, NO, IL-17, IFNy (rodent), TGFP, IFNP, IL-10, NO Glial cell activation and mobilization Reactivation of lymphocytes in CNS Immune effector function Immune regulation Precursor mobilization Neuroprotection remyelination triggering. This has been...

Tgfp13

CXC subfamily (CXCL1-16) CC subfamily (CCL1-28) C subfamily (CL1 Lymphotactin) CX3C subfamily (CX3CL1 Fractalkin) Another group is formed by the type II cytokine receptors and corresponding cytokine ligands, which includes the interferons and the IL-10 family 44 (Table 2.2). All members of the IFN-a p (type I IFN) family show at least 30 homology to one another in their amino acid sequences and they bind to the same heterodimeric receptor 45 In contrast, IFN-y (type II IFN), though sharing some...

Heterodimeric Cytokines

Heterodimeric cytokines consist of a cytokine (member of the hematopoietins) and a soluble receptor protein (member of the class I cytokine receptors) 39 . In contrast to the complexes of soluble receptors and cytokines, which are formed in the circulation, heterodimeric cytokines are formed within the cell. In general, both components are not secreted by synthesizing cells unless they form a complex. To date, four heterodimeric cytokines have been identified IL-12, CLC CLF-1...

Summary

The evidence reviewed here shows that all neurodegenerative disorders are characterized by changes in the expression of cytokines in the brain. It is likely that these changes are neither entirely harmful nor entirely helpful to neuronal function. For this reason, treatments aimed at inhibiting inflammatory processes in neurodegeneration may fail. For example, NSAID treatment in AD has proved ineffective thus far 248 . However, there may be ways to harness cytokine-driven inflammatory processes...

Restriction Of Expression And Internalization

A possibility to restrict cytokine effects to a defined cell population is the control of the expression of cytokine receptors. Because only a limited number of cell types express cytokine receptor on the surface, only these cell types are potential targets for this cytokine. Furthermore, many cytokine receptor proteins are not constitutively expressed, but are only synthesized after appropriate stimulation. The IL-2Ra is only expressed by activated (but not by resting) T-cells. The expression...

B

Inhibition of Trans-Signaling by a molar excess of sgp130 Inhibition of Trans-Signaling by a molar excess of sgp130 FIGURE 3.3 Specific inhibition of the IL-6 sIL-6R transsignal by soluble gp130 (A) IL-6 alone does not bind to the sgp130 dimer. Once bound to the membrane form of the IL-6R, soluble gp130 has no access to the cytokine. Therefore, soluble gp130 is not able to antagonize responses of IL-6 via the membrane form of the IL-6R. (B) Soluble gp130 competes with the membrane-bound gp130...

Cns

Benveniste A CRC title, part of the Taylor & Francis imprint, a member of the Taylor & Francis Group, the academic division of T& F Informa pic. 6000 Broken Sound Parkway NW, Suite 300 2006 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group No claim to original U.S. Government works Printed in the United States of America on acid-free paper

Overview

The elaboration of the vertebrate central nervous system (CNS) results from the complex interplay of cellular interactions that establish positional information, development of cell type specificity, and precise connectivity between distinct cell populations. These diverse responses are orchestrated through the localized expression of a broad range of cytokines and the subsequent responses of target cells. As the molecular nature of specific cellular events in neural development become clear,...

Cil18

Interleukin-18 is a member of the IL-1 family of cytokines, sharing several features with IL-1P such as protein folding structure and caspase-1 mediated processing. IL-18 mRNA is widely expressed, with prominent expression by cells of the myeloid and dendritic lineages 50 . Similar to the IL-1 family, IL-18 signals via a receptor that triggers an IRAK and MyD88 intracellular signaling pathway, leading to NFkB activation 51 . The principal regulation of IL-18 activity is via cleavage of an...

Unique Features Of Cytokine Actions

Cytokine actions have certain characteristic features (Table 2.3). Foremost among these is pleiotropy, the well-known propensity of a single cytokine to affect multiple types of target cells and to elicit diverse biological actions in them. Pleiotropy is a characteristic of all major cytokines as already mentioned TNF, IL-1, the interferons, and TGF-P all display multiple actions on different cells and tissues. Pleiotropy severely limits the therapeutic application of many cytokines because...

Viisome Cytokines Have Different Functional Independent Receptors

Some cytokines possess two different, functional independent receptors. In the case of the TNFaR, these are two proteins (p55, p75). Each of these receptors binds as a homotrimeric complex to the trimeric ligand TNFa and thereby generates an intra-cellular signal 30 . TNFaRs can be found on a variety of cell types. The spectrum of activity of p55 and p75 partially overlaps, but the p55-receptor is responsible for most of the proinflammatory signals, whereas the p75 plays a role in T-cell...

Xcytokine Receptors As Viral Proteins

Pathogenic DNA viruses contain genes with high homology to cellular cytokines or cytokine receptors 41 . Some viruses carry genes coding for antagonistic soluble cytokine receptor molecules. By binding and antagonizing the cytokines, these viral counterparts of the IL-1R, IFNR, and TNFaR suppress the inflammatory and immune-stimulatory effects of these cytokines and thereby protect the virus harboring cell 42 . Interestingly, the genome of the human herpes virus 8 (HHV8), which is associated...

Contributors

Northwestern University Feinberg School of Medicine Chicago, Illinois, USA University of Miami School of Medicine Miami, Florida, USA University of Miami School of Medicine Miami, Florida, USA University of Miami School of Medicine Miami, Florida, USA Albert Einstein College of Medicine Bronx, New York, USA Universit de la M diterran e Aix-Marseille II, France Albert Einstein College of Medicine Bronx, New York, USA University of California San Diego La Jolla, California, USA Emory University...

Cytokine Receptor Proteins

Cytokines bind to specific receptor proteins on the cellular membrane of their target cells. All cytokine receptors are type-I membrane proteins. The receptor proteins can be grouped into distinct families according to their structural features (Table 3.1). TNF-Receptor Family IL-1 Receptor Family Receptors of the IL-2 family specific ligand binding subunits for IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 (in the case of IL-2, two different binding subunits IL-2Ra, IL-2R ) common y subunit (cy)...

Tnfr

FIGURE 3.2 Possible physiological consequences of shedding of cytokine receptor molecules As a first consequence of shedding of cytokine receptor proteins from the cell surface, these cells loose their ability to react to the cognate cytokine. Further consequences depend on the characteristics of the soluble receptor ligand complexes. (A) For the cytokine IL-6, it has been found that the soluble IL-6R acts as an agonistic soluble receptor. The soluble receptor cytokine complex binds to gp130...

Biology Of Microglia

Ifn Tlr3 Cxcl10

Microglia in Normal and Injured CNSs Microglia constitute a distinct glial population in the CNS 1-4 . Unlike neurons and macroglia that are of neuroepithelial origin, microglia are mesodermal (i.e., bone marrow) in origin and seed the brain early in embryogenesis during development, mono-cytes migrate to the brain through the vessels located in specific regions of the brain (called glial fountains in humans). These areas are concentrated around the subven-tricular zones where active...

Evolution Of The Cytokine Field

Although he term cytokine was first used only in the 1970s 8 , the origins of cytokine research can be traced to the middle of the 20th century (reviewed by Oppenheim and Feldmann 9 Vilcek 10 ). Among the earliest described factors are endogenous pyrogen 11 (which is probably identical to the cytokine later termed IL-1), nerve growth factor (NGF) 12 , and interferon 13 . The present field of cytokine research is the result of a fusion of several separate areas of investigation. The arguably...

Brief Survey Of Major Cytokine Families

One way to classify cytokines is to divide them on the basis of their principal functions into mediators of innate immunity, mediators of adaptive immunity, proin-flammatory cytokines, regulators of hematopoiesis, etc. The difficulty with this approach is that most cytokines are pleiotropic, i.e., they generally mediate more than one important function. A more rational and practical basis for the grouping of cytokines is based on their molecular structure and the nature of interacting receptors...

Biology Of Astrocytes

Reactive Astrocytes and CNS Injury The term astrocytes encompasses a diverse population of cells. Although different subpopulations of astrocytes were originally identified based on morphological criteria alone, it is now well recognized that astrocytes, even within well-defined areas of the brain such as the hippocampus, possess qualitatively different ion current phenotypes, display differences in neurotransmitter responsiveness, and may be coupled by different gap junction proteins 74,75...

Cytokines That Direct Immune Responses In The

Antigen-presenting cells (APCs) direct the quality of the emergent T cell response and have the capacity to subvert CNS immune responses toward inflammatory or noninflammatory outcomes, including whether CD4+ T cell activation generates a Th1 or a Th2 response. Although cell-surface interactions e.g., involving B7 family members or CD40, are known to play a role, the major influence on quality of T cell response is through release of specific regulatory cytokines by APCs. Macrophages that are...

Intracellular Redox State Modifies The Action Of Cell Signaling Pathways

The remarkable effects of intracellular redox states on precursor cell division and differentiation, and on oligodendrocyte survival, appear to be explained by a relatively simple hypothesis by which the redox state of a cell is able to selectively amplify the activities of some signaling pathways and dampen the activities of others. Such a hypothesis appears to be well supported by at least some data. Our own studies demonstrated that increasing intracellular glutathione content by as little...

Redox Memory

The above studies are discussed in a developmental context, as it is this context that currently provides our clearest understanding of a likely in vivo relevance, but possible relevance for the analysis of inflammation also needs to be considered. The idea that different precursor cells of the same lineage may have profound differences in their biological properties is a new concept that needs to be examined more broadly in respect to other lineages, to precursor cells of the adult CNS, and...

Oligodendrocytes And Their Ancestry

As this chapter will be concerned not only with oligodendrocytes, but also with the precursor cells that give rise to them, we first briefly summarize current views on the oligodendrocyte lineage and at least some of the signaling molecules that modulate their differentiation. We will use the term precursor cell generically to include both neuroepithelial stem cells (that can give rise to all of the cell types of the CNS) and lineage-restricted progenitor cells (that only give rise to...

Redox Modulation Of The Function Of Oligodendrocyte Precursor Cells

Cytotoxic agents such as TNF-a cause oxidative stress as an important component of their activity. As we have discussed, pharmacological manipulation of redox state can be used to modify the action of these molecules and protect cells. Such analysis, however, treats cells as though redox state was a homogeneous property, with all cells being equal in this regard. In the following sections, we will consider evidence demonstrating that it is overly simplistic to view intracellular redox state as...

Editors

Etty (Tika) Benveniste is professor and chairman of the Department of Cell Biology at the University of Alabama at Birmingham. She received her Ph.D. in immunology from the University of California, Los Angeles, in 1983, and was a postdoctoral fellow in the laboratory of Dr. Jean Merrill, Department of Neurology, UCLA, from 1983 to 1986. Dr. Benveniste has received numerous honors and awards, including NIH Training Grant Fellowships (1982-1983, 1984-1985) a postdoctoral fellowship award from...

Prion Diseases

Human prion diseases include Creutzfeld-Jakob disease (CJD), variant CJD, Kuru, and Gerstmann-Straussler syndrome 211 . These disorders are characterized by a spongiform encephalopathy, deposition of prion protein (PrP) in plaques in the brain, and rapidly progressive dementia 212 . An important neuropathologic feature of prion disease is the accumulation of microglia surrounding prion amyloid plaques 213 . Astrogliosis is also present. The identity of the infectious agent that causes prion...

Antiinflammatory Cytokine Profiles In

During the course of CNS autoimmunity, IL-10 can be produced by macrophages, Th2 cells, B cells and DCs, in addition to astrocytes and microglia 19,53,119,120 . IL-10 has well-documented inhibitory effects on Th1 proliferation and effector cytokine production and is also a potent inhibitor of APC function through its ability to decrease MHC Class II and B7 expression and proinflammatory cytokine and chemokine production 121-123 . In contrast, IL-10 is also known to promote B cell...