Cytokine circuits in brain. Implications for AIDS dementia complex.

This chapter has summarized studies showing that cells of the immune system and glial cells of the CNS use many of the same cytokines as communication signals. Activated astrocytes and microglia are the principal sources of these cytokines in the CNS, although oligodendrocytes are capable of expressing IL-1 and TGF-beta. There is a complex circuitry of interactions mediated by cytokines, especially in the event of blood-brain barrier damage and lymphoid/mononuclear cell infiltration into the CNS. Infiltrating activated macrophages produce cytokines such as IL-1, TNF-alpha, and IL-6, which would trigger glial cells to produce their own cytokines. The activation of astrocytes and microglia to secrete proinflammatory cytokines such as IL-1, TNF-alpha, IL-6, and GM-CsF may contribute to the propagation of intracerebral immune and inflammatory responses initiated by immune cells, as well as enhancement of HIV-1 expression in the CNS. The cytokine cascades ongoing in the CNS could ultimately be suppressed due to the presence of immunosuppressive cytokines such as TGF-beta. Whether immune and inflammatory responses within the CNS are propagated or suppressed depends on a number of parameters, including (a) the activational status of these cells, (b) cytokine receptor levels on glial and immune cells, (c) the presence of cytokines with both immune-enhancing and immune-suppressing effects (IFN-gamma, IL-1, TNF-alpha, IL-6, TGF-beta, CsFs), (d) the concentration and location of these cytokines in the CNS, and (e) the temporal sequence in which a particular cell is exposed to numerous cytokines (see Fig. 1). The ultimate outcome of immunologic and inflammatory events in the CNS, as well as HIV expression, will be determined, in part, by an interplay of the above parameters.