Trends in Neurosciences
Volume 19, Issue 8, August 1996, Pages 331-338
Journal home page for Trends in Neurosciences

Cytokines in inflammatory brain lesions: helpful and harmful

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Abstract

Multiple sclerosis (MS) is thought to be an autoimmune disease. In healthy individuals, the T cells of the immune system, when activated by an infectious agent, regularly traffic across an intact blood-brain barrier, survey the CNS and then leave. In MS, for reasons that are only gradually being understood, certain events in the peripheral immune response and in the brain cause some autoreactive T cells to stay in the CNS. Their presence initiates infiltration by other leukocytes and activation and recruitment of endogenous glia to the inflammatory process, ultimately leading to the destruction of myelin and the myelin-producing cell, the oligodendrocyte, and the dysfunction of axons. The key mediators in the subsequent cycles of histological damage and repair, and clinical relapse and remission are thought to be adhesion molecules, chemokines and cytokines. Trends Neurosci. (1996) 19, 331–338

Section snippets

Extravasation and CNS infiltration by leukocytes

The CNS has historically been considered to be an immunologically privileged site based on the following observations: (1) the CNS is almost completely devoid of a lymphatic system that captures potential antigens; (2) expression of class I and II MHC molecules, which are critical for antigen presentation, is extremely low in the CNS; and (3) the BBB imposes a complex barrier to cell extravasation from circulating blood. The BBB is a specialized vasculature consisting of endothelial cells with

Involvement of chemokines in leukocyte entry into the CNS

The chemokines are small molecular weight (7–10 kDa) secreted proteins that influence the recruitment and activation of leukocytes and other cells to sites of inflammation. Chemokines are the products of three related gene families, members of which exhibit sequence and structural similarities[30]. The two chemokine families that appear to be involved in EAE include the CXC chemokines (α chemokines) that are chemotactic for neutrophils and T cells, and the CC chemokines (β chemokines) that are

The inflammatory oxymoron

What happens after endothelial cells and those perivascular microglia and astrocytes that are closely associated with the BBB mediate the extravasation of blood-borne leukocytes into the brain? It appears that once activated inflammatory cells enter the CNS, they in turn activate parenchymal astrocytes and microglia, thereby ‘recruiting’ them into the inflammatory activity. IFN-γ, TNF-α and IL1β immune complexes acting through the Fc receptor, and complement acting through the C3 receptor (CR3bi

Cytokines in MS and EAE

T cells, particularly CD4+ T helper cells, exist as two distinct subsets based on the cytokines they produce. Th1 cells predominantly produce IL2, IFN-γ, IL12, TNF-α and LT; Th2 cells produce mainly IL4, IL5, IL6 and IL10. Th1 cells are major players in delayed-type hypersensitivity and pro-inflammatory responses by activating cytotoxic T cells and macrophages, while Th2 cells induce B-cell growth and differentiation and thus induce immunoglobulin production. The anti-inflammatory cytokines

Setting the stage for damage

The inflammatory blood macrophage and endogenous brain microglial cell, possibly aided and abetted by the activated astrocyte, are highly incriminated in the actual destruction of myelin as well as in the damage to or death of the myelin-producing cell, the oligodendrocyte[54]. In CNS autoimmune disease, it is likely that T cell-produced IFN-γ activates the effector macrophages or microglia to become armed for attack, and renders the target oligodendrocytes vulnerable to destruction48, 55, 56,

The cytokine-NO connection

IFN-γ induction of NO in rodent and fetal human glia in vitro is augmented by TNF-α and IL1β, but not by IL6, and it is inhibited by IL10 and IL4 (40, 43, 44) (Table 1). Once glia have been activated to produce NO, IL4 and IL10 are less effective as inhibitors43, 56. IL13 and TGF-β, both of which have been shown to inhibit EAE, also inhibit NO production in vitro and in vivo43, 58. IL4 induces NO in resting human monocytes but inhibits NO in activated human macrophages[43].

It is interesting

Cytokines and remyelination

In response to IL1β, among other cytokines, astrocytes produce IL6, LIF, CNTF, BDNF, NGF, IGF-1, PDGF, bFGF and TGF-β, all cytokines and related growth factors that affect the survival, proliferation and maturation of oligodendrocytes[65] (Table 1). Survival of perinatal oligodendrocyte precursors is achieved most effectively by combinations of growth factors from three different families: the LIF family (IL6, CNTF, LIF) plus the neurotrophin family (BDNF, NGF, with NT3 as the key mediator)

Concluding remarks and future directions

Immunohistochemical and in situ hybridization ‘freeze-frame’ analyses of the tissues from MS and EAE brains have provided clues as to the major players in autoimmune inflammatory disease of the CNS. Some of these static clues have already been tested in dynamic cytokine and anti-cytokine intervention in the EAE model in vivo. Nevertheless, many observations on the effects of cytokines on glia have only been made in vitro and need to be confirmed in the animal models of EAE. Additional caution

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