Although reactive glia formation after neuronal degeneration or traumatic damage is one of the hallmarks of central nervous system (CNS) injury, we have little information on the signals that direct activation of resting glia. IL-15, a pro-inflammatory cytokine involved in regulating the response of T and B cells, may be also key for the regulation of early inflammatory events in the nervous system. IL-15 was expressed in the CNS, most abundantly in cerebellum and hippocampus, mainly in astrocytes and in some projection neurons. Using a rodent model of acute inflammatory injury [lipopolysaccharide (LPS) injection], we found enhanced expression of IL-15 in both reactive astroglia and microglia, soon after CNS injury. Blockade of IL-15 activity with an antibody to the cytokine, reversed activation of both glial types, suggesting that IL-15 has a major role in the generation of gliotic tissue and in the regulation of neuroimmune responses. Because IL-15 appears to modulate the inflammatory environment acutely generated after CNS injury, regulating IL-15 expression seems a clear antiinflammatory therapy to improve the outcome of neurodegenerative diseases and CNS trauma.
"The analysis of neurosphere differentiation was performed on cells growing under differentiation conditions (complete medium supplemented with 2% FBS; 4, 7, or 10 d) over glass coverslips coated with poly-llysine . Immunofluorescence staining was performed as previously described (Gomez-Nicola et al., 2008a). The cells were incubated with goat anti-mouse IL-15 (Santa Cruz Biotechnologies), guinea pig anti–mouse DCX (Chemicon), mouse anti–mouse nestin (Abcam), mouse anti–mouse GFAP (Chemicon), rabbit anti–mouse MBP (Abcam), mouse anti–mouse βIII tubulin (Sigma-Aldrich), or mouse anti–mouse O4 (Chemicon, Temecula, CA). "
[Show abstract][Hide abstract] ABSTRACT: The impact of inflammation is crucial for the regulation of the biology of neural stem cells (NSCs). Interleukin-15 (IL-15) appears as a likely candidate for regulating neurogenesis, based on its well-known mitogenic properties. We show here that NSCs of the subventricular zone (SVZ) express IL-15, which regulates NSC proliferation, as evidenced by the study of IL-15-/- mice and the effects of acute IL-15 administration, coupled to 5-bromo-2'-deoxyuridine/5-ethynyl-2'-deoxyuridine dual-pulse labeling. Moreover, IL-15 regulates NSC differentiation, its deficiency leading to an impaired generation of neuroblasts in the SVZ-rostral migratory stream axis, recoverable through the action of exogenous IL-15. IL-15 expressed in cultured NSCs is linked to self-renewal, proliferation, and differentiation. IL-15-/- NSCs presented deficient proliferation and self-renewal, as evidenced in proliferation and colony-forming assays and the analysis of cell cycle-regulatory proteins. Moreover, IL-15-deficient NSCs were more prone to differentiate than wild-type NSCs, not affecting the cell population balance. Lack of IL-15 led to a defective activation of the JAK/STAT and ERK pathways, key for the regulation of proliferation and differentiation of NSCs. The results show that IL-15 is a key regulator of neurogenesis in the adult and is essential to understanding diseases with an inflammatory component.
Molecular biology of the cell 06/2011; 22(12):1960-70. DOI:10.1091/mbc.E11-01-0053 · 4.47 Impact Factor
"Processing of U373MG cell samples and analysis of protein expression were performed as previously described (Gomez-Nicola et al., 2008a). Samples (20 μg protein/lane) were electrophoresed and transferred to nitrocellulose membranes (Whatman GmbH, Dassel, Germany). "
[Show abstract][Hide abstract] ABSTRACT: The high frequency and malignancy of human glioblastomas has stimulated the search for potential therapeutic approaches. The control of the glioma cell proliferation in response to mitogenic signals is one of the most promising antitumoral strategies, and the main target of several therapies. Neurostatin, an O-acetylated derivative of the ganglioside GD1b, has potent antiproliferative activity over the in vitro and in vivo growth of glioma cells. The mechanism of its antitumoral action is the focus of the present study. Using a combined in vitro-in vivo approach, we observed that neurostatin arrested glioma proliferation by inhibiting the expression of cell cycle promoters (i.e. cyclins and CDKs) and promoting the expression of cell cycle inhibitors (i.e. p21 and p27). Neurostatin inhibits epidermal growth factor receptor (EGFR) signaling pathways, blocking the activation of the main promitogenic MAPKs and PI3K pathways. Neurostatin action not only interferes in the cell cycle progression, but also in the protection from apoptosis, and the generation of angiogenic and invasive responses. The antitumoral actions described here point to neurostatin as a novel and promising chemotherapeutic agent for glioma treatment.
"Additionally, western blotting analysis was used to test the CCR7 antibody specificity. The expression of CCR7 was quantified with the help of an image analysis system (AIS, Imaging Research Inc., Linton, England), using a 4× lens, as previously described (Gomez-Nicola et al., 2008a). "
[Show abstract][Hide abstract] ABSTRACT: Neurodegenerative or autoimmune diseases are frequently regulated by chemokines and their receptors, controlling both glial activation and immune cell infiltration. CCL19 and CCL21 have been described to mediate crucial functions during CNS pathological states, regulating both immune cell traffic to the CNS and communication between glia and neurons. Here, we describe the expression pattern and cellular sources of CCR7, receptor of CCL19 and CCL21, in the normal mouse brain. Moreover, we found that CCR7 is upregulated in reactive astrocytes upon intracerebral LPS, regulating early glial reactivity through its ligands CCL19 and CCL21. Our results indicate that CCR7 is playing an important role for the intercellular communication during the inflammatory activation in the CNS.
Journal of neuroimmunology 10/2010; 227(1-2):87-92. DOI:10.1016/j.jneuroim.2010.06.018 · 2.47 Impact Factor
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