Interleukin‐6‐type cytokines in neuroprotection and neuromodulation: oncostatin M, but not leukemia inhibitory factor, requires neuronal adenosine A₁ receptor function

Abstract

J. Neurochem. (2010) 114, 1667–1677. Abstract Neuroprotection is one of the prominent functions of the interleukin (IL)‐6‐type cytokine family, for which the underlying mechanism(s) are not fully understood. We have previously shown that neuroprotection and neuromodulation mediated by IL‐6 require neuronal adenosine A1 receptor (A1R) function. We now have investigated whether two other IL‐6‐type cytokines [oncostatin M (OSM) and leukemia inhibitory factor (LIF)] use a similar mechanism. It is presented here that OSM but not LIF, enhanced the expression of A1Rs (both mRNA and protein levels) in cultured neurons. Whereas the neuroprotective effect of LIF was unchanged in A1R deficient neurons, OSM failed to protect neurons in the absence of A1R. In addition, OSM pre‐treatment for 4 h potentiated the A1R‐mediated inhibition of electrically evoked excitatory post‐synaptic currents recorded from hippocampal slices either under normal or hypoxic conditions. No such effect was observed after LIF pre‐treatment. Our findings thus strongly suggest that, despite known structural and functional similarities, OSM and LIF use different mechanisms to achieve neuroprotection and neuromodulation.

CXCL16 Orchestrates Adenosine A3Receptor and MCP-1/CCL2 Activity to Protect Neurons from Excitotoxic Cell Death in the CNS

“…In addition, its role in modulation of cell metabolism (Cunha, 2001), neuron-glia communication (Boison et al, 2010), and the tuning of growth factor signaling (Gomes et al, 2011) is becoming evident. Indeed, we and others have recently shown that the chemokine CX 3 CL1 and the cytokines IL-6 and OSM are able to drive neuroprotection only in the presence of functional A 1 R (Biber et al, 2008;Lauro et al, 2008Lauro et al, , 2010Moidunny et al, 2010;Cipriani et al, 2011). In particular, IL-6 and OSM potentiate the expression and the function of neuronal A 1 R and therefore the ADO effects on neurotransmission and neuroprotection (Moidunny et al, 2010); on the other hand, CX 3 CL1 neuroprotection is due to ADO release from microglia, activation of A 1 R, and, possibly, the subsequent release of glial-soluble factors that contribute to neuroprotection (Lauro et al, 2010).…”

“…Indeed, we and others have recently shown that the chemokine CX 3 CL1 and the cytokines IL-6 and OSM are able to drive neuroprotection only in the presence of functional A 1 R (Biber et al, 2008;Lauro et al, 2008Lauro et al, , 2010Moidunny et al, 2010;Cipriani et al, 2011). In particular, IL-6 and OSM potentiate the expression and the function of neuronal A 1 R and therefore the ADO effects on neurotransmission and neuroprotection (Moidunny et al, 2010); on the other hand, CX 3 CL1 neuroprotection is due to ADO release from microglia, activation of A 1 R, and, possibly, the subsequent release of glial-soluble factors that contribute to neuroprotection (Lauro et al, 2010). In contrast, in the present work we found that CXCL16 exerts neuroprotection against Glu insult only in the presence of functional A 3 R, the inactivation of all of the other ARs being unable to limit the CXCL16 effect.…”

“…We speculate that the activation of A 3 R is an event downstream of the release of ADO from astrocytes upon CXCL16 treatment; alternatively, also in light of the emerging data on the determinant role of ADO in cytokine neuroprotection (Biber et al, 2008;Lauro et al, 2008Lauro et al, , 2010Moidunny et al, 2010), it can be hypothesized that ADO acts as a synergistic modulator that senses neuronal environment and, together with specific triggering events driven from single cell types, concurs to neuroprotection acting on specific ARs. However, we cannot exclude that other soluble factors might represent key mediators of CXCL16 neuroprotection, since impairing CCL2 activity dramatically reduces, but did not fully abolish, the ability of the chemokine to preserve neurons.…”

“…Acting through four different G-protein-coupled receptors (A 1 R, A 2A R, A 2B R, and A 3 R), extracellular ADO determines the outcome of different brain injuries, mediating neuroprotective or neurotoxic effects. In this regard, we have recently shown that ADO plays a significant role in mediating CX 3 CL1, BDNF, and erythropoietin-mediated neuroprotection through the activation of A 1 receptors (Lauro et al, 2008;, and other reports describe that interleukin-6 (IL-6) and oncostatin M (OSM) require A 1 R functions to exert their neuroprotective effects (Biber et al, 2008;Moidunny et al, 2010).…”

Protection of Pattern Electroretinogram and Retinal Ganglion Cells by Oncostatin M after Optic Nerve Injury

“…Ablation of OSM gene in mouse results in a significant loss of a subset of nociceptive neurons in the dorsal root ganglia (DRG) and defects in pain sensitivity [16]. In addition, OSM is shown to protect neurons from excitotoxic injury in vitro and in vivo [19], [20]. We found recently that OSM protects both rod and cone photoreceptors, and promotes regeneration of cone outer segments in a transgenic rat model of retinal degeneration [21].…”