Astrocytes are the major glial cell within the central nervous system (CNS) and have a number of important physiological properties related to CNS homeostasis. The aspect of astrocyte biology addressed in this review article is the astrocyte as an immunocompetent cell within the brain. The capacity of astrocytes to express class II major histocompatibility complex (MHC) antigens and costimulatory molecules (B7 and CD40) that are critical for antigen presentation and T-cell activation are discussed. The functional role of astrocytes as immune effector cells and how this may influence aspects of inflammation and immune reactivity within the brain follows, emphasizing the involvement of astrocytes in promoting Th2 responses. The ability of astrocytes to produce a wide array of chemokines and cytokines is discussed, with an emphasis on the immunological properties of these mediators. The significance of astrocytic antigen presentation and chemokine/cytokine production to neurological diseases with an immunological component is described.

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One of the characteristic features of microglia is their rapid activation in response to injury, inflammation, neurodegeneration, infection, and brain tumors. This review focuses on the role of the microglia in multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS), and in the animal model of MS, experimental allergic encephalomyelitis (EAE). Microglial activation in MS and EAE is thought to contribute directly to CNS damage through several mechanisms, including production of proinflammatory cytokines, matrix metalloproteinases, and free radicals. In addition, activated microglia serve as the major antigen-presenting cell in the CNS, likely contributing to aberrant immune reactivity at this site. A mechanistic understanding of the way in which microglia are activated and ultimately inhibited is crucial for the formulation of therapeutic modalities to treat MS and other CNS autoimmune disease.

In recent years, there has been increasing evidence that soluble mediators such as cytokines from activated T lymphocytes and macrophages are able to modulate the growth and function of cells found within the central nervous system (CNS), specifically macroglia and microglia cells. Furthermore, glial cells, upon activation, can secrete immunoregulatory factors that influence lymphoid/mononuclear cells as well as the glial cells themselves. Thus the potential exists for bidirectional communication between lymphoid cells and glial cells within the CNS, which in part is mediated via cytokines. This review describes various neurological disease states in which both immune and glial cells may contribute to inflammation and immunologic events occurring in the CNS. The mechanisms by which glial cells both respond to and synthesize a variety of cytokines within the CNS and the capacity of glial cells to acquire major histocompatibility complex antigens and function as antigen-presenting cells within the CNS are described in detail. The implications of these functions, cytokine secretion and antigen presentation, by glial cells are discussed with respect to neurological diseases associated with autoimmunity and/or inflammation.

Macrophages participate in both the amplification of inflammation at the time of injury, and downregulation of the inflammatory response to avoid excess tissue damage. These divergent functions of macrophages are dictated by their microenvironment, especially cytokines, which promote a spectrum of macrophage phenotypes. The M1 proinflammatory phenotype is induced by LPS, IFN-γ and GM-CSF, and IL-4, IL-13 and M-CSF induce anti-inflammatory M2 macrophages. Suppressors Of Cytokine Signaling (SOCS) proteins function as feedback inhibitors of the JAK/STAT signaling pathway, and can terminate innate and adaptive immune responses. In this study, we have evaluated the influence of SOCS3 on macrophage polarization and function. Macrophages obtained from LysMCre-SOCS3fl/fl mice, which lack SOCS3 in myeloid lineage cells, exhibit enhanced and prolonged activation of JAK/STAT pathway compared to macrophages from SOCS3fl/fl mice. Furthermore, SOCS3-deficient macrophages have higher levels of the M1 genes IL-1β, IL-6, IL-12, IL-23 and iNOS, due to enhanced transcriptional activation and chromatin modifications. SOCS3-deficient M1 macrophages also have a stronger capacity to induce Th1 and Th17 cell differentiation than M1 macrophages from SOCS3fl/fl mice. Lastly, LPS-induced sepsis is exacerbated in LysMCre-SOCS3fl/fl mice, and is associated with enhanced STAT1/3 activation and increased plasma levels of M1 cytokines/chemokines such as IL-1β, TNF-α, IL-6, CCL3, CCL4 and CXCL11. These findings collectively indicate that SOCS3 is involved in repressing the M1 proinflammatory phenotype, thereby deactivating inflammatory responses in macrophages.

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Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that contribute to pathological conditions associated with angiogenesis and tumor invasion. MMP-2 is highly expressed in human astroglioma cells, and contributes to the invasiveness of these cells. The human MMP-2 promoter contains potential cis-acting regulatory elements including cAMP response element-binding protein, AP-1, AP-2, PEA3, C/EBP, and Sp1. Deletion and site-directed mutagenesis analysis of the MMP-2 promoter demonstrates that the Sp1 site at ؊91 to ؊84 base pairs and the AP-2 site at ؊61 to The matrix metalloproteinases (MMPs) 1 are a family of structurally related zinc-dependent endopeptidases capable of degrading extracellular matrix components (for review, see Refs. 1-3). The MMP family includes collagenases, gelatinases, stromelysins, membrane-type metalloproteinases, matrilysin, and metalloelastase. A hallmark of invasive tumors is their ability to degrade the surrounding extracellular matrix, resulting in a compromised matrix organization and disruption of tissue boundaries. A number of in vitro and in vivo studies have documented a direct correlation between high levels of expression of MMP and an increased invasive capacity of tumor cell lines (1, 4 -6). Glioblastoma multiforme is a highly malignant central nervous system tumor that is extremely refractory to therapy due to the rapid growth and local invasive potential of these tumors (for review, see Refs. 7 and 8). This rapid infiltrative growth prevents successful surgical resection of glioblastoma multiformes. The ability of glioma cells to invade the surrounding tissue has been attributed to their secretion of MMPs. In vitro, human glioma cell lines express a variety of MMPs, in particular the type IV collagenases MMP-2 and MMP-9 (9 -15). In vivo studies have also demonstrated the expression of MMP-2 and MMP-9 in human gliomas (11, 12, 16 -18); MMP-2 and MMP-9 expression was the highest in high grade gliomas (glioblastoma multiforme, anaplastic astroglioma) compared with non-invasive low grade astrogliomas and normal brain (11,18,19). Importantly, the invasiveness of glioma cells in vitro correlates with high levels of MMP-2 expression (9,12,14,15,20). A number of strategies have been utilized to modulate MMP-2 expression/activity, then assess subsequent changes in invasive potential. The MMP-2 proenzyme is activated by cell surface-associated membrane-type metalloproteinases (21, 22). Transfection of U251.3 glioma cells with membrane-type metalloproteinases-1 leads to activation of the MMP-2 proenzyme and enhanced invasion as assessed by Matrigel assay (23), as well as remodeling of the extracellular matrix in vitro (24). We have recently demonstrated that two cytokines, tumor necrosis factor-␣ and interferon-␥, inhibit MMP-2 expression in glioma cells, which results in decreased invasiveness of these cells (15). Collectively, these results highlight the important role of MMP-2 in the invasive potential of astroglioma cells.The activity of MMP-2 is regulated by seve...