THE ROLE OF TUMOR-NECROSIS-FACTOR, INTERLEUKIN-6, INTERFERON-GAMMA AND INDUCIBLE NITRIC-OXIDE SYNTHASE IN THE DEVELOPMENT AND PATHOLOGY OF THE NERVOUS-SYSTEM

Proinflammatory cytokines, tumour necrosis factor (TNF)-alpha, interfe ron (IFN)-gamma and interleukin (IL)-6, have multiple effects in the c entral nervous system (CNS) not strictly cytotoxic being involved in c ontrolling neuronal and glial activation, proliferation, differentiati on and survival, thus influencing neuronal and glial plasticity, degen eration as well as development and regeneration of the nervous system. Moreover, they can contribute to CNS disorders, including multiple sc lerosis, Alzheimer's disease and human immunodeficiency virus-associat ed dementia complex. Recent results with deficient mice in the express ion of those cytokines indicate that they are in general more sensible to insults resulting in neural damage. Some of the actions induced by TNF-alpha, and IFN-gamma, including both beneficial and detrimental, are mediated by inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) production. NO produced by iNOS may be beneficial by promot ing the differentiation and survival of neurons. IL-6 does not induce iNOS, explaining why this cytokine is less often involved in this dual role protection/pathology. Some of the proinflammatory as well as the neurotrophic effects of those cytokines also involve upregulation of cell adhesion molecules (CAM). Those apparently conflicting results ma y be reconciled considering that proinflammatory cytokines are involve d in promoting the disease, mostly by inducing expression of CAM leadi ng to alteration of the blood-brain barrier integrity, whereas they ha ve a protective role once disease is established due to its immunosupp ressive or neurotrophic role. Understanding the dichotomy pathogenesis /neuroprotection of those cytokines may provide a rationale for better therapeutic strategies. (C) 1998 Elsevier Science Ltd. All rights res erved.