It has been known for more than a decade that astro cytes are the major source for LIF in the CNS. However, the factors responsible for the regulation of LIF expression in these cells are still largely unknown. It is well known that stressed neurons release nucleotides selleck chem such as ATP and adenosine. Re cently, it was demonstrated that astrocytes increase LIF production and release in response to ATP receptor stimulation. In this study, the authors demonstrate that neurons during action potentials can secrete ATP, which triggers LIF production in astrocytes. This ATP dependent upregulation of LIF by astrocytes is respon sible for the promotion of oligodendrocyte mediated myelination around neuronal axons. ATP is also known to be secreted by neurons during stressful conditions such as seizure, ischemia and hypoxia.

However, when we blocked adenosine Inhibitors,Modulators,Libraries receptors with the non selective antagonist caffeine, or with specific A2A A2B re ceptor antagonists, the effect of glutamate stressed neur onal supernatants on LIF expression in astrocytes was absent, suggesting that adenosine, but not ATP, is re sponsible for astrocytic LIF production during glutamate induced neuronal stress. Thus, it might be hypothesized that depending on the CNS status, astro cytic LIF expression and secretion Inhibitors,Modulators,Libraries is differentially regu lated, during normal neuronal activity and development ATP is involved whereas during neuronal insults, adeno sine might enhance LIF secretion by astrocytes.

Several studies have demonstrated the involvement of adenosine A2B receptors in the regulation of IL 6 expression in various cell types in vitro as well as in vivo, suggesting that A2B receptors might also be essential in the regulation of other IL 6 type cytokines. Our results show that adenosine dependent LIF regulation is mediated Inhibitors,Modulators,Libraries through the A2B receptor, since no increase in LIF expression was found in cultured astrocytes from A2B receptor deficient mice. Instead NECA caused a down regulation of LIF mRNA after 8 and 24 hours in these cells, indicating that knock ing out A2B receptors may have unmasked an inhibitory effect on LIF mRNA expression of an unidentified ad enosine receptor. Whether or not this might explain the very short lived effect of NECA on Inhibitors,Modulators,Libraries LIF mRNA expres sion in wild type astrocytes is at the moment unclear and a subject of future investigations.

We furthermore demonstrated that A2B mediated LIF expression is dependent on the PKC, but not the Inhibitors,Modulators,Libraries PKA pathway. These data are in line with the study of Aloisi and colleagues, which demonstrated that LIF modulation by pro inflammatory cytokines in human astrocytes was mediated through PKC activation. Moreover, PKC has also been shown to be essential in www.selleckchem.com/products/Roscovitine.html IL 6 regulation, revealing a prominent role for PKC in the signaling pathway controlling LIF gene expression.