The cytokines interleukin-1 (IL-1) and'interleukin-6 (IL-6) are proinflammatory mediators of the immune system present in the central nervous system. Excessive glial cytokine production contributes to neurodegenerative processes such as Alzheimer's Disease (AD). A mechanism by which IL-1 activates glia is unknown, as are the effects of inhibitory neurotransmitters on the regulation of IL-1 signaling. We have demonstrated that IL-1 stimulates IL-6 release from C6 astrocytoma cells. Inhibition of p38 mitogen- activated protein kinase (MARK) compromises IL-1 action in C6 cells, as do the inhibitory neurotransmitters somatostatin (SRIF) and gamma-aminobutyric acid (GABA). We propose to delineate a p38-driven pathway underlying IL-1 action in C6 cells and primary rat astrocytes, and identify potential post-receptor mechanisms through which inhibitory transmitters interfere with IL-1-driven signaling. A primary hypothesis is that p38 is essential for IL-1-stimulated IL-6 release from C6 cells, and that SRIF and GABA abrogate this by blockade of intracellular signals through recruitment of one or more MAPK/SAPK pathways. We will initially describe the IL-1 activation of p38 MARK (and SAPKs such as ERK and JNK). We will also assess the influence of SRIF and GABA on concurrent kinase activation and IL-6 release by IL-1; possible ntranuclear targets downstream of IL-1 signaling (e.g., ATF-2, c-Jun, kappaB) will be examined as well. Finally, effects of inhibitory transmitters on transactivation factors will be probed; the actions of SRIF and GABA will be related to specific receptor subtypes via potential mimicry by analogs with established receptor selectivity profiles. Our results should reveal probable cellular mechanisms by which SRIF and GABA restrict glial elaboration of inflammatory cytokines. Though once considered only protective cellular elements in the CNS, activated astroctyes and microglia deliver lethal, neurotoxic insults during AD. Understanding molecular mechanisms by which neurotransmitters can prevent such toxic glial activation will provide new strategies for pharmacological abrogation of glia-mediated neuronal injury. ? ?
| Vo, Van; Tanthmanatham, Ontida; Han, Haesook et al. (2013) Synthesis of [PtCl2(4,4'-dialkoxy-2,2'-bipyridine)] complexes and their in vitro anticancer properties. Metallomics 5:973-87 |
| Roach Jr, Joseph D; Aguinaldo, Grant T; Jonnalagadda, Kaumudi et al. (2008) Gamma-aminobutyric acid inhibits synergistic interleukin-6 release but not transcriptional activation in astrocytoma cells. Neuroimmunomodulation 15:117-24 |
| Spangelo, Bryan L; Roach, Joseph D; Hadi, Freidun et al. (2007) Thymosin fraction-5 possesses antiproliferative properties in HL-60 human promyelocytic leukemia cells: characterization of an active peptide. Ann N Y Acad Sci 1112:305-16 |
