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Pro- and anti-inflammatory cytokines regulate the ERK pathway: Implication of the timing for the activation of microglial cells

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Abstract

Pro-inflammatory molecules induce glial activation and the release of potentially detrimental factors capable of generating oxidative damage, such as nitric oxide (NO) and superoxide anion (O2 ·−. Activated glial cells (astrocytes and microglia) are associated to the inflammatory process in neurodegenerative diseases. A strong inflammatory response could escape endogenous control becoming toxic to neurons and contributing to the course of the disease. We evaluated in a hippocampal cells-microglia co-culture model, if the pro-inflammatory condition induced by lipopolysaccharide + interferon-γ (LPS+IFN-γ) promoted damage directly or if damage was secondary to glial activation. In addition, we explored the effect of the anti-inflammatory cytokine transforming growth factor-β1 (TGF-β1), and pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) on the regulation of the inflammatory response of microglia. We found that LPS+IFN-γ-induced damage on hippocampal cultures was dependent on the presence of microglial cells. In hippocampal cultures exposed to LPS+IFN-γ, TGF-β1 was induced whereas in microglial cell cultures LPS+IFN-γ induced the secretion of IL-1β. TGF-β1 and IL-1β but not TNF-α decreased the NO production by 70–90%. PD98059, an inhibitor of MAP kinase (MEK), reduced the IFN-γ-induced NO production by 40%. TGF-β1 and IL-1β reduced the IFN-γ-induced phosphorylation of ERK1,2 by 60% and 40%, respectively. However, the effect of IL-1β was observed at 30 min and that of TGF-β1 only after 24 h of exposure. We propose that acting with different timing, TGF-β1 and IL-1β can modulate the extracellular signal-regulated kinase ERK1,2, as a common element for different transduction pathways, regulating the amplitude and duration of glial activation in response to LPS+IFN-γ. Cross-talk among brain cells may be key for the understanding of inflammatory mechanisms involved in pathogenesis of neurodegenerative diseases.

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References

  • Akiyama H, S Barger, S Barnum, B Bradt, J Bauer, G Cole, N Cooper, P Eikelenboom, M Emmerling, B Fiebich, C Finch, S Frautschy, W Griffin, H Hampel, M Hull, G Landreth, L Lue, R Mrak, I Mackenzie, P McGeer, M O’Banion, J Pachter, G Pasinetti, C Plata-Salaman, J Rogers, R Rydel, Y Shen, W Streit, R Strohmeyer, I Tooyoma, F Van Muiswinkel, R Veerhuis, S Walker, B Wegrzyniak, G Wenk and T Wyss-Coray (2000) Inflammation and Alzheimer’s disease.Neurobiol. Aging 21, 383–421.

    Article  PubMed  CAS  Google Scholar 

  • Basu A, J Krady and S Levinson (2004) Interleukin-1: A master regulator of neuroinflammation.J. Neurosci. Res. 78, 151–156.

    Article  PubMed  CAS  Google Scholar 

  • Benveniste E, V Nguyen and G O’Keefe (2001) Immunological aspects of microglia: relevance to Alzheimer’s disease.Neurochem. Int. 39, 381–391.

    Article  PubMed  CAS  Google Scholar 

  • Blanchette J, M Jaramillo and M Olivier (2003) Signalling events involved in interferon-γ-inducible macrophage nitric oxide generation.Immunology 108, 513–522.

    Article  PubMed  CAS  Google Scholar 

  • Bruce-Keller A, J Keeling, J Keller, F Huang, S Camondola and M Mattson (2000) Antiinflammatory effects of estrogen on microglial activation.Endocrinol.141, 3646–3656.

    Article  CAS  Google Scholar 

  • Cáceres A, G Banker, O Steward, L Binder and M Payne (1984) MAP2 is localized to the dendrites of hippocampal neurons which develop in culture.Brain Res. 315, 314–318.

    PubMed  Google Scholar 

  • Chao CC, S Hu and PK Peterson (1995) Modulation of human microglial cell superoxide production by cytokines.J. Leukoc. Biol. 58, 35–70.

    Google Scholar 

  • Ding M, B St. Pierre, J Parkinson, P Medberry, J Wong, N Rogers, L Ignaro and J Merril (1997) Inducible nitric-oxide synthase and nitric oxide production in human foetal astrocytes and microglia.J. Biol. Chem. 272, 11327–11335.

    Article  PubMed  CAS  Google Scholar 

  • Flanders K, R Ren and C Lippa (1998) Transforming growth factor-betas in neurodegenerative disease.Prog. Neurobiol.54, 71–85.

    Article  PubMed  CAS  Google Scholar 

  • Giulian D and T Baker (1986) Characterization of ameboid microglia isolated from developing mammalian brain.J. Neurosci. 6, 2163–2178.

    PubMed  CAS  Google Scholar 

  • Giulian D and M Corpuz (1993) Microglial secretion products and their impact on the nervous system.Adv. Neurol.59, 315–320.

    PubMed  CAS  Google Scholar 

  • Giulian D and J Ingemann (1988) Colony-stimulating factors as promoters of ameboid microglia.J. Neurosci. 8, 4707–4717.

    PubMed  CAS  Google Scholar 

  • Giulian D, K Vaca and M Corpuz (1993) Brain glial release factors with opposing actions upon neuronal survival.J. Neurosci. 13, 29–37.

    PubMed  CAS  Google Scholar 

  • Giulian D, J Li, X Li, J George and P Rutecki (1994) The impact of microglia-derived cytokine upon gliosis in the CNS.Dev. Neurosci. 16, 128–136.

    Article  PubMed  CAS  Google Scholar 

  • Gleizes P, J Munger, I Nunes, J Harpel, R Mazzieri, I Noguera and D Rifkin (1997) TGF-β latency: biological significance and mechanisms of activation.Stem Cells 15, 190–197.

    Article  PubMed  CAS  Google Scholar 

  • Han I-O, K-W Kim, J-H Ryu and W-K Kim (2002) p38 Mitogen-activated protein kinase mediates lipopolysaccharide, not inter-feron-γ, -induced inducible nitric oxide synthase expression in mouse BV2 microglial cells.Neurosci. Lett. 325, 9–12.

    Article  PubMed  CAS  Google Scholar 

  • Hazuda D, R.L. Webb, P Simon and P Young (1998) Purification and characterization of human recombinant precursor interleukin 1 beta.J. Biol. Chem. 264, 1689–1693.

    Google Scholar 

  • Henrich-Noack P, J Prehn and J Krieglstein (1996) TGF-β1 protects hippocampal neurons against degeneration caused by transient global ischemia.Stroke 27, 1609–1614.

    PubMed  CAS  Google Scholar 

  • Herrera-Molina R and R von Bernhardi (2005) Transforming growth factor-β1 produced by hippocampal cells modulates microglial reactivity in culture.Neurobiol. Dis. 19, 229- 236.

    Article  PubMed  CAS  Google Scholar 

  • Hu S, WS Sheng, PK Peterson and CC Chao (1995) Cytokines modulation of murine microglial cell superoxide production.Glia 13, 45–50.

    Article  PubMed  CAS  Google Scholar 

  • Kaur Ch, A-J Hao, Ch-H Wu and E-A Ling (2001) Origin of microglia.Microsc. Res. Tech. 54, 2–9.

    Article  PubMed  CAS  Google Scholar 

  • Lee S, W Liu, C Brosnan and D Dickinson (1994) GM-CSF promotes proliferation of human fetal and adult microglia in primary cultures.Glia 12, 309–318.

    Article  PubMed  CAS  Google Scholar 

  • Lieb K, S Engels and B Fiebich (2003) Inhibition of LPS-induced iNOS and NO synthesis in primary rat microglial cells.Neurochem. Int. 42, 131–137.

    Article  PubMed  CAS  Google Scholar 

  • Ling E and W Wong (1993) The origin and nature of ramified and amoeboid microglia: a historical review and current concepts.Glia 7, 9–18.

    Article  PubMed  CAS  Google Scholar 

  • Marcus J, S Karackattu, M Fleegal and C Summers (2003) Cytokine-stimulated inducible nitric oxide synthase expression in astroglia: role of Erk Mitogen-activated protein kinase and NF-κB.Glia 41, 152–160.

    Article  PubMed  Google Scholar 

  • Martin L, C Pardo, L Cork and D Price (1994) Synaptic pathology and glial responses to neuronal injury precede the formation of senile plaques and amyloid deposits in the aging cerebral cortex.Am. J. Pathol. 145, 1358–1381.

    PubMed  CAS  Google Scholar 

  • McCartney-Francis N and S Wahl (2002) Dysregulation of IFN-γ signaling pathways in the absence of TGF-β1.J. Immunol.169, 5941–5947.

    PubMed  CAS  Google Scholar 

  • McGeer P and E McGeer (1995) The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases.Brain Res. Rev. 21, 195–218.

    Article  PubMed  CAS  Google Scholar 

  • McGeer P and E McGeer (2001) Inflammation, autotoxicity and Alzheimer disease.Neurobiol. Aging 22, 799–809.

    Article  PubMed  CAS  Google Scholar 

  • Meda L, P Baron and G Scarlato (2001) Glial activation in Alzheimer’s disease: the role of Aβ and its associated proteins.Neurobiol. Aging 22, 885–893.

    Article  PubMed  CAS  Google Scholar 

  • Mrak R, J Sheng and S Griffin (1995) Glial cytokines in Alzheimer’s disease.Human Pathology 26, 816–823

    Article  PubMed  CAS  Google Scholar 

  • Munger J, J Harpel, P Gleizes, R Mazzieri, I Nunes and D Rifkin (1997) Latent transforming growth factor-β: structural features and mechanisms of activation.Kidney Int. 51, 1376–1382.

    Article  PubMed  CAS  Google Scholar 

  • O’Brien M, L Lenke, J Lou, K Bridwell and M Joyce (1994) Astrocyte response and transforming growth factor-beta localization in acute spinal cord injury.Spine 19, 2321–2329.

    Article  PubMed  CAS  Google Scholar 

  • Patel AJ, S Gunasekera, A Jen and H Rohan (1996) Beta-amyloid-mediated inhibition of redox activity (MTT reduction) is not an indicator of astroglial degeneration.NeuroReport 7, 2026–2030.

    Article  PubMed  CAS  Google Scholar 

  • Pfeiffer S, A Gorren, K Schmidt, E Werner, B Hanser, D Bohle and B Mayer (1997) Metabolic fate of peroxynitrite in aqueous solution.J. Biol. Chem. 272, 3465–3470.

    Article  PubMed  CAS  Google Scholar 

  • Pyo H, I Jou, S Jung, S Hong and E-H Joe (1998) Mitogen-activated protein kinases activated by lipopolysaccharide and β-amyloid in cultured rat microglia.NeuroReport 9, 871–874.

    Article  PubMed  CAS  Google Scholar 

  • Ramírez G, R Toro, H Döbeli and R von Bernhardi (2005) Protection of rat primary hippocampal cultures from Aβ cytotoxicity by pro-inflammatory molecules is mediated by astrocytes.Neurobiol Dis. 19, 243–254.

    Article  PubMed  CAS  Google Scholar 

  • Rook G (1985) A simple method for the solubilisation of reduced NBT, and its use as a colorimetric assay.J. Immunol. Methods 82, 161–167.

    Article  PubMed  CAS  Google Scholar 

  • Rothwell N and G Luheshi (2000) Interleukin 1 in the brain: biology, pathology and therapeutic target.Trends Neurosci. 23, 618–625.

    Article  PubMed  CAS  Google Scholar 

  • Schubert P, T Morino, H Miyazaki, T Ogata, Y Nakamura, C Marchini and S Ferroni (2000) Cascading glia reactions: a common pathomecanism and its differentiated control by cyclic nucleotide signalling.Ann. NY. Acad. Sci. 903, 24–33.

    Article  PubMed  CAS  Google Scholar 

  • Shappell N (2003) Ergovaline toxicity on CACO-2 cells as assessed by MTT, alamar blue and DNA assays.In vitro Cell Dev. Biol-animal 39, 329–335.

    Article  CAS  Google Scholar 

  • Sheng J, S Bora, G Xu, D Borchelt, D Price and V Koliatos (2003) Lipopolysaccharide-induced-neuroinflammation increases intra-cellular accumulation of amyloid precursor protein and amyloid beta peptide in APPswe transgenic mice.Neurobiol. Dis. 14, 133–145.

    Article  PubMed  CAS  Google Scholar 

  • Van Eldik L (2001) Glia and Alzheimer’s disease.Neurochem. Int. 39, 329–331.

    Article  PubMed  Google Scholar 

  • Vegeto E, C Bonincontro, G Polli, A Sala, S Viappiani, F Nardi, A Brusadelli, B Viviani, P Ciana and A Maggi (2001) Estrogen prevents the lipopolysaccharide-induced inflammatory response in microglia.J. Neurosci. 21, 1809–1818.

    PubMed  CAS  Google Scholar 

  • Vincent V, F Tielders and A Van Dam (1997) Inhibition of endotoxin induced nitric oxide synthase production in microglial cells by the presence of astroglial cells: a role for transforming growth factor β.Glia 19, 190–198.

    Article  PubMed  CAS  Google Scholar 

  • von Bernhardi R and J Eugenín (2004) Microglial activity to - amyloid is modulated by astrocytes and pro-inflammatory factors.Brain Res. 1025, 186–193.

    Article  CAS  Google Scholar 

  • von Bernhardi R, G Ramírez, H Matile and H Döbeli (2001) Immobilized APP constructs: a tool for thein vitro screening of glial cells reactivity.Europ. J. Neurosci. 14, 946–956.

    Article  Google Scholar 

  • von Bernhardi R, K Saud and R Herrera-Molina (2004) Modulation of the production of NO and O2-induced by IFN-γ in glial cells by anti- and pro-inflammatory cytokines: the role of ERK and STAT pathways. Shanghai Int. Conf. Physiol. Biophys. Abstract book, p 127.

  • Weiner H and D Selkoe (2002) Inflammation and therapeutic vaccination in CNS diseases.Nature 420, 879–884.

    Article  PubMed  CAS  Google Scholar 

  • Zhu Y, S Roth-Eichhorn, N Braun, C Culmsee, A Rami and J Krieglstein (2000) The expression of transforming growth factor-beta 1 (TGF-β1) in hippocampal neurons: a temporary upregulated protein level after transient forebrain ischemia in the rat.Brain Res. 866, 286–298.

    Article  PubMed  CAS  Google Scholar 

  • Zhu Y, G Yang, B Ahlemeyer, L Pang, X Che and C Culmsee (2002) Transforming growth factor-ß1 increases bad phosphorylation and protects neurons against damage.J. Neurosci. 22, 3898–3909.

    PubMed  CAS  Google Scholar 

  • Zhu Y, C Culmsee, S Klumpp and J Krieglstein (2004) Neuroprotection by transforming growth factor-β1 involves activation of nuclear factor-κB through phosphatidylinositol-3-OH kinase/Akt and mitogen-activated protein kinase extracellular-signal regulated kinase 1,2 signaling pathways.Neuroscience 123, 897–906.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Marcoleta 391, Santiago, CHILE

    Katherine Saud, Rodrigo Herrera-Molina & Rommy Von Bernhardi

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  1. Katherine Saud
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  2. Rodrigo Herrera-Molina
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  3. Rommy Von Bernhardi
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Correspondence to Rommy Von Bernhardi.

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Saud, K., Herrera-Molina, R. & Von Bernhardi, R. Pro- and anti-inflammatory cytokines regulate the ERK pathway: Implication of the timing for the activation of microglial cells. neurotox res 8, 277–287 (2005). https://doi.org/10.1007/BF03033981

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