1 Introduction
4 Interleukin 1 Family
4.1 Signaling Pathways and Expression of IL-1 Family and its Receptors in Normal CNS
Members of the IL-1 family include IL-1α, IL-1β, IL-18, and the interleukin IL-1 receptor antagonist (IL-1ra) as well as 6 other proteins with unknown functions (reviewed in Allan et al., 2005). IL-1α is mostly cell-membrane associated and shares little sequence homology with IL-1β. IL-1β and IL-18 are closely related; both possess a similar three-dimensional structure, and their respective precursor forms are inactive until cleaved by the intracellular cysteine protease caspase-1. IL-1α and IL-1β mediate peripheral and central inflammation by binding to the IL-1 type I receptor (IL-1RI) and activating NFkB and stress-activated MAPK signaling cascades. IL-1ra binds to the same receptor and can modulate IL-1 activity. In addi-tion, IL-1α, IL-1β, and IL-1ra bind also to IL-1R2, while IL-18 binds to IL-1R related protein. Recent data suggests that while IL-1α and IL-1β induce identical IL-1 signaling pathways, IL-1β is significantly more potent than IL-1α in stimulat-ing IL-6 release in primary mixed glia (Andre et al., 2005); these differential actions in the CNS raise the possibility that there may be other IL-1 receptor(s) in the brain. Numerous reports have correlated the presence of increased IL-1 in the injured or diseased brain, and its effects on neurons and nonneuronal cells in the CNS, but the importance of IL-1 signaling in normal brain function has only recently been recognized (Basu et al., 2004). Despite their low levels in normal brain, the IL-1 family of proteins has now been shown to exert numerous biological effects in the brain, including induction of acute-phase proteins needed in neuroim-mune responses and activation of many inflammatory processes with direct actions on CNS neurons. Evidence that IL-1 is higher in the brain during sleep and that spontaneous sleep can be reduced by IL-1ra implicate this cytokine in sleep physiology. In addition, increased expression of IL-1 after the induction of hippocampal long-term potentiation (LTP) and reversal by IL-1ra establish a connection to synaptic plasticity (reviewed in Allan et al., 2005).
4.2 Role of IL-1 Family in Disease
A number of polymorphisms in the genes that encode IL-1α 1A), IL-1β (IL-1B) and IL-1ra (IL-1RA; IL-1RN) have been implicated in CNS diseases (reviewed in Allan et al., 2005), however many associations are weak or have not been replicated. In contrast, there is substantial evidence that IL-1 and IL-18 are involved in the neuronal injury that occurs in chronic neurodegenerative disorders and the acute damage seen after stroke and brain trauma (Allan et al., 2005). The molecular basis of these cytokine effects remains to be elucidated. For example, in vivo administration of IL-1β (60 µg/kg, i.p.) induced the phosphorylation of ERK1/2 in
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neurons, astrocytes and microglia in areas at the interface between brain and blood or cerebrospinal fluid: meninges, circumventricular organs, endothelial-like cells of the blood vessels, and in brain nuclei involved in behavioral depression, fever and neuroendocrine activation (paraventricular nucleus of the hypothalamus, supraoptic nucleus, central amygdala and arcuate nucleus). In addition, recent studies support a crucial role for IL-18 in mediating neuroinflammation and neurodegeneration in the CNS under pathological conditions, such as bacterial and viral infection, autoimmune demyelinating disease, and hypoxic-ischemic, hyper-oxic and traumatic brain injuries (Felderhoff-Mueser et al., 2005). In psychologi-cally and physipsychologi-cally stressed organisms, IL-18 influences pathological and physiological processes by participating in stress-related disruption of host defenses (Sekiyama et al., 2005).
The use of transgenic and gene-knockout mice has provided the opportunity to substantiate the physiological significance of IL-1-family members in the CNS (Table 2). Mice deficient in IL-1α and IL-1β show significantly reduced ischemic cell death, whereas deletion of either IL-1α or IL-1β alone does not protect. It has also been demonstrated that IL-1 exacerbates ischemic injury in mice in the absence of IL-1R1, again suggesting the existence of novel IL-1 receptors in the brain. Mice that are deficient in IL-1R1 sleep less, show deficits in synaptic plasticity, and per-form worse in a spatial memory task than control animals (reviewed in Allan et al., 2005). Although most of the neurodegenerative effects of IL-1 are thought to be mediated through IL-1β, data from genetic models implicate IL-1α in excitotoxic cell death as well. Furthermore, intrastriatal administration of the excitotoxin AMPA in the rat brain leads to marked increases in IL-1 cytokine expression in the frontoparietal cortex and drastically exacerbates neuronal loss in this region.
Enhancement of cell death pathways by IL-1 results in increased limbic seizures (Seripa et al., 2003). IL-1β (Cunningham et al., 1996; Curran et al., 2003) and IL-18 (Curran and O’Connor, 2001) have also been reported to have inhibitory effects on LTP. From human and animal studies, we can conclude that IL-1β and IL-18 participate in fundamental inflammatory processes that increase during the aging process as well as in the febrile response (see below). Lastly, transgenic mouse models with astrocyte-directed overexpression of the IL-1ra have demon-strated an important role of IL-1 signaling in the CNS. Two additional GFAP-hsIL-1ra strains have been generated and characterized further: GILRA2 and GILRA4.
These strains show a brain-specific expression of the hsIL-1ra at the mRNA and protein levels in the CSF which are 13- and 28-fold higher respectively, compared to wild-type (Lundkvist et al., 1999).
4.2.1 Febrile Response
Fever is a normal adaptation in response to a pyrogenic stimulus (tissue injury, pathogenic bacteria, etc.) resulting in the generation of cytokines and prostagland-ins (Boutin et al., 2003). The body produces a wide array of pyrogenic cytokines such as interleukins (IL-1, IL-6), interferon, and TNF which are sensed by the
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circumventricular organ system (CVOS) lying at the interface of the blood–brain barrier. When pyrogenic cytokines are detected by the CVOS, prostaglandin syn-thesis, especially cyclo-oxygenase-dependent prostaglandin E2, is induced as part of the febrile response. Once the hypothalamus receives the signal, autonomic, endocrine, and behavioral processes are activated until the hypothalamic set-point is reset downward as a consequence of a reduction in pyrogen content or antipyretic therapy, with subsequent heat loss. The febrile response elicited by IL-1β (50 ng/
mouse i.c.v.) was abolished in hsIL-1ra-overexpressing animals, suggesting that the central IL-1 receptors were occupied by antagonist.
4.2.2 Traumatic Brain Injury and Epilepsy
Increases in IL-1 early after brain injury lead to increases in neuronal excitability through modulation of the balance between excitatory and inhibitory synaptic transmission, induction of neurotoxin production, leukocyte infiltration, activation of microglial cells and astrocytes (reviewed by Allan et al., 2005).
4.2.3 Ischemic Stroke and Excitotoxicity
IL-1 exerts a number of diverse actions in the brain, and it is currently well accepted that it contributes to experimentally induced neurodegeneration. IL-1 is one of the key modulators of the inflammatory response after cerebral stroke, and its activity is critically regulated by its receptor antagonist IL-1ra. Much of this is based on studies using IL-1ra, which inhibits cell death caused by ischemia, brain injury, or excitotoxins (Hailer et al., 2005; Pinteaux et al., 2006).
4.2.4 Inflammation in Aging
Patients with mutations in the NALP3 gene, which controls the activity of caspase-1, readily secrete more IL-1β and IL-18 and suffer from systemic inflammatory diseases (Dinarello, 2006). Patients with defects in this gene have high circulating concentrations of IL-6, serum amyloid, and C-reactive protein, each of which decrease rapidly upon blockade of the IL-1 receptor, which suggests that IL-1β contributes to the elevation of these markers as part of the inflammatory mecha-nisms associated with aging.
4.2.5 Alzheimer’s Disease
IL-1-dependent inflammation may contribute to the pathophysiology of AD since it is expressed at abnormally high levels by glial cells in AD in the vicinity of amy-loid plaques and can lead to neuronal injury and activation of p38 MAPK pathways
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and phosphorylation of tau (Sheng et al., 2001; Li et al., 2003; Cacquevel et al., 2004). IL-1 promoter polymorphisms were among several gene polymorphisms in inflammation-related genes suspected to compose a susceptibility profile for AD risk that also included IL-6, TNF, α-2-macroglobulin (A2M), and α-1-antichymotrypsin (AACT). Although several individual reports of polymorphisms in genes of various IL-1 family ligands (IL-1α -889, IL-1β -511, IL-1β + 3953) suggested associations between specific alleles and AD in that their presence appeared to increase the risk for AD or modified the age-at-onset of AD (Du et al., 2000; Grimaldi et al., 2000;
Nicoll et al., 2000; Kolsch et al., 2001; Murphy et al., 2001; Ehl et al., 2003), other studies revealed no significant associations between these polymorphisms and AD (Ki et al., 2001; Green et al., 2002). Therefore, as is the case for other cytokines, fur-ther evaluation of the association of IL-1 gene polymorphisms with AD and their role in pathogenesis is needed.
4.2.6 Parkinson’s Disease
The CSF of PD patients has been reported to contain high concentrations of IL-1 (Blum-Degen et al., 1995), but the role of IL-1β in this disease is still unclear. Patients with AD and Lewy body dementia showed co-localization of IL-1β -expressing micro-glia with neurons that were highly immunoreactive for β-amyloid precursor protein (βAPP) and contained both Lewy Bodies and neurofibrillary tangles (Grigoryan et al., 2000), raising the possibility that the clinical and neuropathological overlap between AD and PD may be mediated by IL-1β (Μrak and Griffin 2007). Although numerous in vitro and in vivo studies have demonstrated that IL-1β contributes to the degeneration of neurons in SNpc (reviewed in Allan et al., 2005), a recent report suggested it may also have a neuroprotective role by eliciting GDNF release from astrocytes under acute inflammatory conditions (Saavedra et al., 2007). Consistent with this finding, IL-1β promoter polymorphisms appear to be protective in PD (Nishimura et al., 2001, 2005);
additional studies will be needed to confirm these findings.
4.3 IL-1 Family Members as Therapeutic Targets
Because the IL-1 family coordinates both systemic and CNS host defense responses to pathogens and to injury and is at or near the top of the hierarchical cytokine sig-naling cascade in the CNS that activates neuroinflammation, it may provide an attractive target for therapeutic intervention in diseases where the latter contributes to destruction of vulnerable neuronal populations. For example, IL-1β is the major inducer of central cyclo-oxygenase 2 (COX2) activity and as such has an important role in production of prostaglandin E2 and other prostanoids which sensitize peripheral nociceptive terminals and produce localized pain hypersensitivity. In contrast, inhibiting IL-1 actions (by intracerebroventricular (i.c.v) injection of IL-1ra, neutralizing antibody to IL-1 or caspase-1 inhibitor) significantly reduces ischemic
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brain damage (Boutin et al., 2001, 2003). Similarly, controlling the caspase-1 activating pathway to suppress IL-18 levels may provide preventative means against stress-related disruption of host defenses.