Oncostatin M and leukemia inhibitory factor in excitotoxicity

PhD ceremony: Mr. S. Moidunny, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Oncostatin M and leukemia inhibitory factor in excitotoxicity

Promotor(s): prof. K.P.H. Biber, prof. H.W.G.M. Boddeke

Faculty: Medical Sciences

Oncostatin M (OSM) and leukemia inhibitory factor (LIF) are cytokines belonging to the interleukin-6 (IL-6) family that are produced in excess under neuro-degenerating conditions of the central nervous system (CNS). Several recent reports suggest a neuroprotective role of these cytokines, but the underlying mechanisms are not yet understood. Since toxicity caused by the neurotransmitter glutamate (excitotoxicity) is a major cause for the death of neurons in the CNS, we investigated in detail the role of OSM and LIF in excitotoxicity. Our research provides evidence that indeed both OSM and LIF protect neurons of mouse cortex and hippocampus against excitotoxicity. OSM mediates neuroprotection by enhancing the level of a membrane protein in neurons called adenosine A1 receptor (A1R), whereas the neuroprotective effect of LIF is independent of A1R activity or expression. In addition, we show that neurons under excitotoxic-stress induce expression and release of the neuroprotective LIF from astrocytes (major source of LIF in the CNS). We also provide the first evidence on molecular events that controls the expression and release of LIF from astrocytes during neuronal excitotoxicity. Furthermore, our research suggests a “dual” role played by OSM in excitotoxicity based on the target cell of action, since OSM inhibits expression and activity of glutamate-transporters in astrocytes, thereby promoting neuronal excitotoxicity. Preventing degeneration of neurons under pathological conditions remains a challenge and our results demonstrate that cytokines of the IL-6 family are potential candidates for the treatment of chronic and acute brain damage.