Interleukin1 and neurodegeneration

IL-1 is a monokine (macrophage cytokine) whose expression is regulated at multiple steps [49,50]. Following transcriptional activation and translation, generation of mature (active) IL-1 requires processing of proIL-1 by IL-1 converting enzyme (ICE: caspase-1). Microglial expression of IL-1 is readily induced in vitro by a number of different stimuli, including HIV-1, hypoxia, P-amyloid, LPS, and cytokines (including IL-1 itself) [51-53] (and unpublished observations), as well as activation through the TLRs and scavenger receptors discussed above. IL-1 is unique in the sense that its own antagonist, IL-1 receptor antagonist (IL-1ra), is produced endoge-nously by macrophages. In the CNS, microglial cells express IL-1ra and recombinant IL-1ra is a potent and specific inhibitor of IL-1 action [54]. Microglial IL-1ra expression is subject to regulation by microbial components and cytokines. In general, proinflammatory cytokines that induce IL-1 also induce IL-1ra; however, anti-inflammatory cytokines such as IL-4 and IFNP have opposing effects on the expression of IL-1

and IL-1ra: they inhibit IL-1 while inducing IL-1ra, shifting the balance to an IL-1ra-predominant state [54].

Microglial IL-1 expression is found associated with pathologic lesions in stroke, AD, HIVE, and other inflammatory conditions. In human stroke, microglial IL-1 expression is one of the earliest measurable changes in the brain (Figure 1.3) [55]. IL-1 expression is specifically induced in amyloid plaque-associated microglial cells in AD [56]. IL-1 expression can be induced as a result of primary insult but also by secondary activation of microglia due to a number of factors (hypoxia, cytokines, and growth factors, etc.) that often coexist in these brains. For example, in HIVE, IL-1 expression is found not only in HIV-1-infected microglia and macrophages, but also in uninfected, activated microglia found throughout the brain (Figure 1.3) [57].

The role of IL-1 in neurodegeneration has been extensively studied in acute and chronic neurodegenerative diseases. In animal models of stroke or trauma, proin-flammatory cytokines are induced rapidly after acute CNS insult and are expressed in a temporal and spatial pattern consistent with their involvement in subsequent neuronal death. Modulation of exogenous and endogenous cytokines in vivo and in vitro has yielded conflicting results: overall, IL-1 appears to contribute directly to neurodegeneration, whereas TNFa and IL-6 can both enhance and inhibit neuronal injury (for review, see [58]). Administration of IL-1ra has been shown to reduce the infarct size in animal models of stroke [59,60]. Caspase-1 knock out mice demonstrate reduced amounts of neuronal damage from ischemic and excitotoxic origin compared to wild-type mice [61]. In mice deficient in the expression of the IL-1 receptor (IL-1RI), the emergence of ameboid microglia and the expression of inflammatory mediators (IL-1, IL-6, and cyclooxygenase-2) are suppressed and delayed following penetrating brain injury [62]. Collectively, these in vivo results support the role of IL-1 in brain inflammation, reactive gliosis, and neuronal damage.

Alzheimer's disease is a chronic neurodegenerative disease in which the role of IL-1 in neuronal damage has been extensively investigated. The intimate association of IL-1-expressing microglia with P-amyloid in senile plaques suggested that IL-1 might trigger an inflammatory cascade that ultimately contributes to neuronal demise [56,63,64]. Exposure of cultured cells to insoluble aggregates of P-amyloid leads to production of a number of inflammatory molecules, including proinflammatory cytok-ines and nitric oxide. IL-1 mediates the pathological effects of microglia on neurons such as abnormal phosphorylation of tau and reduced synthesis of synaptophysin [65]. Polymorphisms in the IL-1 a and IL-1P genes have also been linked to the increased risk for AD [64].

IL-1's role in neuronal damage is firmly established in a number of in vitro systems. Several mechanisms (direct and indirect) may underlie IL-1-mediated neurotoxicity, with some notable differences between human and rodent systems. For example, IL-1 may contribute to glutamate-mediated neurodegeneration by modulating NMDA receptor function. In rat hippocampal neurons, pretreatment with IL-1 increases NMDA receptor function through activation of tyrosine kinases and subsequent NR2A/B subunit phosphorylation [66]. In a series of in vivo and in vitro experiments using the HIV-1 glycoprotein gp120 as the insult, Corasaniti and colleagues identified IL-1 as the neurotoxic cytokine [67]. They showed that injection of gp120 to rat brain or stimulation of the chemokine receptors CXCR4 or CCR5

in vitro by gp120 led to the induction of IL-1P and the activation of caspase-1 and COX-2 expression, culminating in neuronal death. Using recombinant IL-1P in primary cultures of human neurons and glia, we and others have found that IL-1 is toxic to neurons [68,69]. The IL-1-induced neurotoxicity was enhanced by the Th1 cytokine IFN but reduced by inhibitors of TNFa or nitric oxide (NO) synthase. These studies support the idea that NO alone is a weak neurotoxin and that the conditions in which both NO and a proinflammatory cytokine (TNFa) are coex-pressed lead to significant damage to the CNS [70]. Importantly, these studies have delineated striking species differences in the cytokine-induced neurotoxicity cascade. Whereas LPS, IL-1, or TNFa can all trigger neurotoxicity in rodent cultures, the induction of neurotoxicity in human brain cell cultures appears to be dependent on the presence of IL-1 [68,69,71,72]. Furthermore, IL-1-activated astrocytes are an important mediator of neurotoxicity in the human system by producing NO and TNFa [73]. The redundancy in the IL-1-inducing signals for human microglia, the lack of expression of IL-1 in human astrocytes, and the number of genes regulated by IL-1 in human astrocytes [32] all point to the unique role of microglial IL-1 in human pathologies.

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