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NEUTROPHIL-ACTIVATING peptide-1/interleukin-8 (NAP-1/IL-8) is a cytokine synthesized by various cell types. In the immune system NAP-l/IL-8 is part of an immune cascade initiated by IL-1 production. NAP-1/ IL-8 affects hypothalamic function and its production is suppressed by steroids. Therefore, it might be expected that NAP-1/IL-8 would be produced in brain areas involved in the control of the hypothalamic-pituitary-adrenocortical axis (HPA). NAP-1/IL-8 mRNA was localized by in situhybridization in the paraventricular nucleus of the hypothalamus and hippocampus. Those areas also express the genes encoding interleukin-1-alpha (IL-1α), IL-1β, IL-1 receptors, and IL-1 receptor antagonist (IL-1ra). This suggests that an immune cascade, which is well characterized in the immune system, may exist in brain, in areas of relevance to the regulation of stress-related neuroendocrine function.

THE mechanism by which IL-1β exerts its actions in the brain during systemic inflammation is not fully understood, as neither IL-1 receptor gene expression nor IL-1 binding have been identified in significant levels in key areas that respond to IL-1β. Having hypothesized that perivascular nitric oxide (NO) might modulate the effects of systemic IL-1β in the brain, we studied the expression of the genes encoding for IL-1β, the signal-transducing IL-1 receptor type I (IL-1RI) and inducible NO synthase (iNOS) constitutively and during systemic inflammation in vascular and perivascular regions of the rat brain. Our results show that IL-1RI is constitutively expressed at the interface of the vascular wall and perivascular glia. During systemic inflammation there is induction of IL-1 (3 gene expression in the vascular wall, accompanied by perivascular induction of iNOS mRNA. We conclude that during systemic inflammation vascular IL-1 (3, binding to vascular and perivascular IL-1RI receptors, may induce perivascular iNOS gene expression, leading to the production of NO and modulation of the effects of IL-1 (3 in the brain. We propose that the vascular and perivascular induction of iNOS mRNA by IL-1β might represent a mechanism for the modulation of the central nervous system effects of peripheral inflammatory mediators.