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Blockade of IL‐15 activity inhibits microglial activation through the NFκB, p38, and ERK1/2 pathways, reducing cytokine and chemokine release
Author(s) -
GomezNicola Diego,
ValleArgos Beatriz,
NietoSampedro Manuel
Publication year - 2010
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.20920
Subject(s) - proinflammatory cytokine , chemokine , microbiology and biotechnology , biology , microglia , cytokine , signal transduction , inflammation , p38 mitogen activated protein kinases , immunology , mapk/erk pathway
Reactive glia formation is one of the hallmarks of damage to the CNS, but little information exists on the signals that direct its activation. Microglial cells are the main regulators of both innate and adaptative immune responses in the CNS. The proinflammatory cytokine IL‐15 is involved in regulating the response of T and B cells, playing a key role in regulating nervous system inflammatory events. We have used a microglial culture model of inflammation induced by LPS and IFNγ to evaluate the role of IL‐15 in the proinflammatory response. Our results indicate that IL‐15 is necessary for the reactive response, its deficiency (IL‐15‐/‐) leading to the development of a defective proinflammatory response. Blockade of IL‐15, both with blocking antibodies or with the ganglioside Neurostatin, inhibited the activation of the NFκB pathway, decreasing iNOS expression and NO production. Inhibiting IL‐15 signaling also blocked the activation of the mitogen‐activated protein kinase (MAPK) pathways ERK1/2 and p38. The major consequence of these inhibitory effects, analyzed using cytokine antibody arrays, was a severe decrease in the production of chemokines, cytokines and growth factors, like CCL17, CCL19, IL‐12, or TIMP‐1, that are essential for the development of the phenotypic changes of glial activation. In conclusion, activation of the IL‐15 system seems a necessarystep for the development of glial reactivity and the regulation of the physiology of glial cells. Modulating IL‐15 activity opens the possibility of developing new strategies to control gliotic events upon inflammatory stimulation. © 2009 Wiley‐Liss, Inc.