Modulation of hippocampal acetylcholine release - a potent central action of interleukin-2

The potential of the T-cell growth factor interleukin-2 (IL-2) to modulate the release of ACh from rat hippocampus was studied in vitro, as a means to investigate the possible functional significance of this cytokine in the CNS. Hippocampal slices were superfused with Krebs' buffer medium, and endogenous ACh released into the superfusate was measured using a radioenzymatic assay. Recombinant human IL-2 present during a stimulation with 25 mM KCl altered, in a concentration-dependent manner, the evoked transmitter release. At a concentration of 15 U/ml (< or = 1 nM), IL-2 inhibited ACh release by more than 50% of the control level (evoked ACh release from the untreated contralateral hemispheres). Inhibition was observed within 20 min of tissue exposure to IL-2 and lasted for up to 1 hr. The inhibitory effect of IL-2 was reversible since transient tissue exposure to IL-2 did not affect subsequent evoked ACh release. IL-2 at this concentration also significantly decreased evoked ACh in frontal cortical slices, but was ineffective in the parietal cortex and striatum, revealing that IL-2 selectively modulates the release of ACh from certain, but not all, cholinergic nerve terminals in the CNS. At very low concentrations (1.5 mU/ml, < or = 0.1 pM), IL-2 transiently increased hippocampal evoked ACh release, resulting in a biphasic dose-response profile with no significant effect observed at 0.015 mU/ml (< or = 1 fM). Other cytokines (IL-1 alpha, IL-3, IL-5, IL-6, interferon alpha), tested in hippocampal slice incubations, failed to modulate ACh release

Elevation of basal intracellular calcium as a central element in the activation of brain macrophages (microglia): suppression of receptor-evoked calcium signaling and control of release function

Microglia-brain macrophages are immune-competent cells of the CNS and respond to pathologic events. Using bacterial lipopolysaccharide (LPS) as a tool to activate cultured mouse microglia, we studied alterations in the intracellular calcium concentration ([Ca 2+]i) and in the receptor-evoked generation of transient calcium signals. LPS treatment led to a chronic elevation of basal [Ca 2+]i along with a suppression of evoked calcium signaling, as indicated by reduced [Ca 2+]i transients during stimulation with UTP and complement factor 5a. Presence of the calcium chelator BAPTA prevented the activation-associated changes in [Ca 2+]i and restored much of the signaling efficacy. We also evaluated downstream consequences of a basal [Ca 2+]i lifting during microglial activation and found BAPTA to strongly attenuate the LPS-induced release of nitric oxide (NO) and certain cytokines and chemokines. Furthermore, microglial treatment with ionomycin, an ionophore elevating basal [Ca 2+]i, mimicked the activation-induced calcium signal suppression but failed to induce release activity on its own. Our findings suggest that chronic elevation of basal [Ca 2+]i attenuates receptor-triggered calcium signaling. Moreover, increased [Ca 2+]i is required, but by itself is not sufficient, for release of NO and certain cytokines and chemokines. Elevation of basal [Ca 2+]i could thus prove a central element in the regulation of executive functions in activated microglia

Microglia as a source and target of cytokines

Cytokines constitute a significant portion of the immuno- and neuro-modulatory messengers that can be released by activated microglia. By virtue of potent effects on resident and invading cells, microglial cyto- and chemokines regulate innate defense mechanisms, help the initiation and influence the type of immune responses, participate in the recruitment of leukocytes to the CNS, and support attempts of tissue repair and recovery. Microglia can also receive cyto- and chemokine signals as part of auto- and paracrine communications with astrocytes, neurons, the endothelium, and leukocyte infiltrates. Strong responses and modulatory influences can be demonstrated, adding to the emerging view that microglial behavior is highly dependent on the (cytokine) environment and that reactions to a challenge may vary with the stimulation context. In principle, microglial activation aims at CNS protection. However, failed microglial engagement due to excessive or sustained activation could significantly contribute to acute and chronic neuropathologies. Dysregulation of microglial cytokine production could thereby promote harmful actions of the defense mechanisms, result in direct neurotoxicity, as well as disturb neural cell functions as they are sensitive to cytokine signaling

Microglia: active sensor and versatile effector cells in the normal and pathologic brain

Microglial cells constitute the resident macrophage population of the CNS. Recent in vivo studies have shown that microglia carry out active tissue scanning, which challenges the traditional notion of 'resting' microglia in the normal brain. Transformation of microglia to reactive states in response to pathology has been known for decades as microglial activation, but seems to be more diverse and dynamic than ever anticipated-in both transcriptional and nontranscriptional features and functional consequences. This may help to explain why engagement of microglia can be either neuroprotective or neurotoxic, resulting in containment or aggravation of disease progression. Moreover, little is known about the heterogeneity of microglial responses in different pathologic contexts that results from regional adaptations or from the progression of a disease. In this review, we focus on several key observations that illustrate the multi-faceted activities of microglia in the normal and pathologic brain

Microglia

Microglia--the macrophage equivalent of the CNS--safeguards and supports neuronal functions. Threats to the CNS homeostasis can trigger a rapid transformation of these cells from a normally "resting" into alerted and "activated" states. Microglia primarily serves the tissue defence and protection when participating in mechanisms of innate and adaptive immunity. On the contrary, excessive acute or chronic microglial activation can provoke severe neuronal and glial damage by carrying or fuelling destructive cascades. Several factors and conditions have already been identified that maintain the resting phenotype or organize and control the activation process. Cells are thereby able to recognize a dangerous signal as well as to sense functional disturbance. Microglial activation is also proving a much more variable and adaptive process than previously noticed. Aiming at microglia as a therapeutic target, research may focus on intracellular pathways that are probably common to activation scenarios as triggered by various receptor systems. Certain signalling elements may have key roles in the cytosolic integration of sensory inputs and a conversion into programs of executive performance. As the integrative aspect of microglial activation becomes illuminated hope builds up also on strategies for selective interference with harmful outcomes in favour of the--phylogenetically approved--beneficial potential of these fascinating cells