HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Covacu, R. Articles by Brundin, L. PubMed PubMed Citation Articles by Covacu, R. Articles by Brundin, L. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Stem Cells

TLR Activation Induces TNF- Production from Adult Neural Stem/Progenitor Cells¹

Ruxandra Covacu^2,*, Lisa Arvidsson, Åsa Andersson^*, Mohsen Khademi^*, Helena Erlandsson-Harris, Robert A. Harris^*, Mikael A. Svensson, Tomas Olsson^* and Lou Brundin^*

^* Department of Clinical Neurosciences, Division of Neuroimmunology, Department of Neurosurgery, and Department of Medicine, Division of Rheumatology, Karolinska Institutet, Stockholm, Sweden

Adult neural stem cells (NSCs) are believed to facilitate CNS repair and tissue regeneration. However, it is not yet clear how these cells are influenced when the cellular environment is modified during neurotrauma or neuroinflammatory conditions. In this study, we determine how different proinflammatory cytokines modulate the expression of TLR2 and TLR4 in NSCs and how these cells respond to TLR2 and TLR4 agonists. Primary cultures of neural stem/progenitor cells isolated from the subventricular zone of brains from adult Dark Agouti rats were exposed to 1) supernatants from activated macrophages; 2) proinflammatory cytokines IFN-, TNF-, or both; and 3) agonists for TLR2 and TLR4. Both TLR2 and TLR4 were expressed during basal conditions and their mRNA levels were further increased following cytokine exposure. TLR4 was up-regulated by IFN- and this effect was reversed by TNF-. TLR2 expression was increased by supernatants from activated macrophages and by TNF-, which synergized with IFN-. TLR agonists induced the expression of TNF- mRNA. Importantly, TNF- could be translated into protein and released into the supernatants where it was quantified by cytokine ELISA. In conclusion, we demonstrate that NSCs constitutively express TLR2 and TLR4 and that their expression is increased as a consequence of exposure to proinflammatory mediators. Additionally, activation of these receptors can induce production of proinflammatory cytokines. These findings suggest that NSCs may be primed to participate in cytokine production during neuroinflammatory or traumatic conditions.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Torsten and Ragnar Söderberg Foundation, Montel Williams Foundation, The Swedish Society for Neurologically Disabled, and Karolinska Institutet.

² Address correspondence and reprint requests to Dr. Ruxandra Covacu, Karolinska Hospital, Center for Molecular Medicine, L8-04, Neuroimmunology Unit, Karolinska Institutet, S-171 76 Stockholm, Sweden. E-mail address: Ruxandra.Covacu{at}ki.se

³ Abbreviations used in this paper: NSC, neural stem cell; EAE, experimental autoimmune encephalomyelitis; MS, multiple sclerosis; LTA, lipoteichoic acid; SVZ, subventricular zone; GFAP, glial fibrillary acidic protein.

⁴ The online version of this article contains supplemental material.