Interleukin-6 Enhances Expression of Adenosine A1 Receptor mRNA and Signaling in Cultured Rat Cortical Astrocytes and Brain Slices

Abstract

The inhibitory neuromodulator adenosine is released in the brain in high concentrations under conditions of exaggerated neuronal activity such as ischemia and seizures, or electroconvulsive treatment. By inhibiting neural overactivity, adenosine counteracts seizure activity and promotes neuronal survival. Since stimulation of adenosineAdenosine, as a metabolite of ATP, nature's general energy source, has acquired early in evolution the general function of signaling and counteracting a dysbalance of energy supply and demand (Newby 1984). In the brain, adenosine acts as an inhibitory neuromodulator, which is released under conditions of neuronal activity and reduces this activity by inhibition of transmitter release and postsynaptic hyperpolarisation. Brain damage, e.g., by stroke, ischemia, and seizures leads to a pronounced increase in extracellular adenosine (for review see Rudolphi and Schubert 1996) which counteracts seizure activity (Dragunow 1988) and promotes neuronal survival (Deckert and Gleiter 1994;Picano and Abbracchio 1998;Dux et al. 1990).In addition to its role as an endogenous anticonvulsant and neuroprotective agent, adenosine is now recognized as an important regulator of sleep and wakefulness (for review see Porkka-Heiskanen 1999 (van Calker et al. 1978(van Calker et al. , 1979, but more recent findings have revealed coupling of adenosine receptors to other signaling systems including the phosphoinositol system, potassium, and calcium channels (for review see Fredholm et al. 1994;Ralevic and Burnstock 1998). Adenosine mediates neuroprotection by inhibiting presynaptically the release of several neurotransmitters including the excitatory neurotransmitter glutamate (Ribeiro 1995). Postsynaptically, adenosine increases conductances of various K ϩ -and Cl Ϫ -channels, which hyperpolarize the membrane potential and counteract a transmitter induced depolarisation with a subsequent reduction of Ca 2 ϩ -influx and stabilization of the Mg 2 ϩ blockage of NMDA receptors (Rudolphi et al. 1992a,b;Rudolphi and Schubert 1996). Most, if not all, of these actions of adenosine are mediated via the adenosine A 1 receptor, whereas the role of the other adenosine receptor subtype in neuroprotection is less clear (Schubert et al. 1997;Abbracchio and Cattabeni 1999;Heurteaux et al. 1995). Accordingly, upregulation of adenosine A 1 receptors by chronic treatment with A 1 -antagonists increases the neuroprotective effect of adenosine (Sutherland et al. 1991; Rudolphi et al. 1992a,b).Upregulation of adenosine A1-receptors is also observed after treatments that exert antidepressive effects in humans such as seizures and electroconvulsive treatment (ECT) (Newman et al. 1984;Gleiter et al. 1989;Angelatou et al..1993;Pagonopoulou et al. 1993), REM sleep deprivation (Yanik and Radulovacki 1987), and chronic treatment with carbamazepine (Daval et al. 1989;Biber et al. 1999;van Calker et al. 2000). While the upregulation by carbamazepine of adenosine A 1 receptors is readily comprehensible from carbamazepine's selective antag...

Interleukin-6 Upregulates Neuronal Adenosine A1 Receptors: Implications for Neuromodulation and Neuroprotection

“…We previously showed that IL-6 induces the expression of adenosine A 1 receptors in glia cells (Biber et al, 2001), where even modest changes in A 1 receptor expression cause marked changes in adenosine A 1 receptor-meditated signaling (Biber et al, 1997). Now, we extended these findings to neurons, the brain cells where the predominant expression of adenosine A 1 receptors occurs (Onodera and Kogure, 1988;Ulas et al, 1993;Swanson et al, 1995) and where adenosine acts to refrain excitatory transmission and to protect from uncoordinated firing (Dragunow, 1988;Dunwiddie and Masino, 2001).…”

“…Tissue was lysed in guanidinium isothiocyanate/mercaptoethanol buffer and total RNA was extracted with one phenol/chloroform step (Chomczynski and Sacchi, 1987) and transcribed into cDNA as described (Biber et al, 2001). …”

“…We have previously shown that IL-6 induces the upregulation of mRNA transcripts for the adenosine A 1 receptor in the brain (Biber et al, 2001). Functional adenosine A 1 receptors fulfill important neuroprotective properties during excitotoxic conditions, causing the inhibition of glutamate release from the presynaptic terminal (Barrie and Nicholls, 1993), the downregulation of postsynaptic NMDA receptor-mediated currents (de Mendonça et al, 1995;Sebastião et al, 2001) and the stabilization of the postsynaptic cell membrane (Trussell and Jackson, 1985;Gerber and Gahwiler, 1994).…”

The Antiepileptic Potential of Nucleosides

“…It has also been supported by the demonstration of an epilepsy-induced decrease in A 1 receptor expression in chronic seizures [67,[158][159][160]228] and adaptive changes in Ado receptors after seizures [111]. Activation of A 2B receptors by elevated Ado levels may induce the release of proinflammatory interleukin-6 (IL-6) from astrocytes leading to increased expression of A 1 receptors and their functions in the brain [229,230], which may explain (i) the increase of A 1 receptor expression after seizures parallel with increasing Ado level and (ii) the higher level of IL-6 in the brain areas (e.g., in the hippocampus and cortex) of epileptic patients and rats [186,[231][232][233], which may have a protective effect against subsequent seizures [230]. In addition, an increase in A 1 receptor density has been demonstrated in the epileptic tissue, for example, in PTZ kindling mice and kainic-acid-treated rats, which may also be an adaptive/protective mechanism against hyperexcitability-induced seizures and convulsions [96,230,[234][235][236][237][238][239].…”

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

“…Concurrently, IL-6 can decrease IL-1 and TNF-α synthesis in activated monocytes and may increase the production of IL-1Ra and soluble TNF receptors to decrease the inluence of these largely pro-inlammatory cytokines [204,205]. IL-6's neuroprotective efects have been shown to be mediated via the upregulation of adenosine A1 receptors on cells [206]. IL-6 also potentially aids in tissue remodeling and recovery through the initiation of astrogliosis and angiogenesis after injury [202,207,208].…”