Abstract
We investigated the molecular mechanisms underlying the deterioration of macrophage inflammatory responses in middle-aged mice, focusing on the age-related reduction in protein synthesis rate. Peritoneal macrophages were isolated from male BALB/c mice aged 2 months (young) and 12 months (middle-aged), and stimulated with lipopolysaccharide (LPS). At the protein level, LPS-stimulated pro-inflammatory cytokine release and intracellular accumulation of bactericidal mediators from macrophages were clearly lower in middle-aged mice than in young mice. However, LPS caused a marked increase in the mRNA expression of these genes in the macrophages of both young and middle-aged mice. Moreover, LPS induced comparable phosphorylation levels of signaling proteins downstream of toll-like receptor (TLR) in young and middle-aged mice. In contrast, levels of the inactive (phosphorylated) form of eukaryotic initiation factor 2α (eIF-2α) were higher in macrophages from middle-aged mice than in macrophages from young mice. Suppression of the LPS-stimulated inflammatory responses observed in middle-aged mice could be mimicked by treating the murine macrophage RAW264.7 cells with salubrinal, an inhibitor of the phosphatase that dephosphorylates eIF-2α. In conclusion, post-transcriptional suppression of macrophage inflammatory responses during middle age requires phosphorylation of eIF-2α.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Boehmer ED, Goral J, Faunce DE, Kovacs EJ (2004) Age-dependent decrease in toll-like receptor 4-mediated proinflammatory cytokine production and mitogen-activated protein kinase expression. J Leukoc Biol 75:342–349. doi:10.1189/jlb.0803389
Boehmer ED, Meehan MJ, Cutro BT, Kovacs EJ (2005) Aging negatively skews macrophage TLR2- and TLR4-mediated pro-inflammatory responses without affecting the IL-2-stimulated pathway. Mech Ageing Dev 126:1305–1313. doi:10.1016/j.mad.2005.07.009
Cecílio CA, Costa EH, Simioni PU, Gabriel DL, Tamashiro WM (2011) Aging alters the production of iNOS, arginase and cytokines in murine macrophages. Braz J Med Biol Res 44:671–681. doi:10.1590/S0100-879X2011007500067
Chelvarajan RL, Collins SM, Van Willigen JM, Bondada S (2005) The unresponsiveness of aged mice to polysaccharide antigens is a result of a defect in macrophage function. J Leukoc Biol 77:503–512. doi:10.1189/jlb.0804449
Chelvarajan RL, Liu Y, Popa D, Getchell ML, Getchell TV, Stromberg AJ, Bondada S (2006) Molecular basis of age-associated cytokine dysregulation in LPS-stimulated macrophages. J Leukoc Biol 79:1314–1327. doi:10.1189/jlb.0106024
Dever TE, Chen JJ, Barber GN, Cigan AM, Feng L, Donahue TF, London IM, Katze MG, Hinnebusch AG (1993) Mammalian eukaryotic initiation factor 2α kinases functionally substitute for GCN2 protein kinase in the GCN4 translational control mechanism of yeast. Proc Natl Acad Sci U S A 90:4616–4620
Dunston CR, Griffiths HR (2010) The effect of ageing on macrophage toll-like receptor-mediated responses in the fight against pathogens. Clin Exp Immunol 161:407–416. doi:10.1111/j.1365-2249.2010.04213.x
Gomez CR, Nomellini V, Faunce DE, Kovacs EJ (2008) Innate immunity and aging. Exp Gerontol 43:718–728. doi:10.1016/j.exger.2008.05.016
Hamamura K, Tanjung N, Yokota H (2013) Suppression of osteoclastogenesis through phosphorylation of eukaryotic translation initiation factor 2 alpha. J Bone Miner Metab 31:618–628. doi:10.1007/s00774-013-0450-0
Hussain SG, Ramaiah KV (2007) Reduced eIF2α phosphorylation and increased proapoptotic proteins in aging. Biochem Biophys Res Commun 355:365–370. doi:10.1016/j.bbrc.2007.01.156
Kawai T, Akira S (2011) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34:637–650. doi:10.1016/j.immuni.2011.05.006
Kohut ML, Senchina DS, Madden KS, Martin AE, Felten DL, Moynihan JA (2004) Age effects on macrophage function vary by tissue site, nature of stimulant, and exercise behavior. Exp Gerontol 39:1347–1360. doi:10.1016/j.exger.2004.07.001
Kovacs EJ, Palmer JL, Fortin CF Jr, Fülöp T, Goldstein DR, Linton PJ (2009) Aging and innate immunity in the mouse: impact of intrinsic and extrinsic factors. Trends Immunol 30:319–324. doi:10.1016/j.it.2009.03.012
Krishnamoorthy T, Pavitt GD, Zhang F, Dever TE, Hinnebusch AG (2001) Tight binding of the phosphorylated α subunit of initiation factor 2 (eIF2α) to the regulatory subunits of guanine nucleotide exchange factor eIF2B is required for inhibition of translation initiation. Mol Cell Biol 21:5018–5030. doi:10.1128/MCB. 21.15.5018-5030.2001
Ladiges W, Morton J, Blakely C, Gale M (2000) Tissue specific expression of PKR protein kinase in aging B6D2F1 mice. Mech Ageing Dev 114:123–132. doi:10.1016/S0047-6374(00)00097-X
Morel M, Couturier J, Lafay-Chebassier C, Paccalin M, Page G (2009) PKR, the double stranded RNA-dependent protein kinase as a critical target in Alzheimer’s disease. J Cell Mol Med 13:1476–1488. doi:10.1111/j.1582-4934.2009.00849.x
Panda A, Arjona A, Sapey E, Bai F, Fikrig E, Montgomery RR, Lord JM, Shaw AC (2009) Human innate immunosenescence: causes and consequences for immunity in old age. Trends Immunol 30:325–333. doi:10.1016/j.it.2009.05.004
Pyo CW, Lee SH, Choi SY (2008) Oxidative stress induces PKR-dependent apoptosis via IFN-γ activation signaling in Jurkat T cells. Biochem Biophys Res Commun 377:1001–1006. doi:10.1016/j.bbrc.2008.10.103
Rattan SI, Derventzi A, Clark BF (1992) Protein synthesis, posttranslational modifications, and aging. Ann N Y Acad Sci 663:48–62. doi:10.1111/j.1749-6632.1992.tb38648.x
Rattan SI (1996) Synthesis, modifications, and turnover of proteins during aging. Exp Gerontol 31:33–47. doi:10.1016/0531-5565(95)02022-5
Renshaw M, Rockwell J, Engleman C, Gewirtz A, Katz J, Sambhara S (2002) Cutting edge: impaired toll-like receptor expression and function in aging. J Immunol 169:4697–4701
Segev Y, Michaelson DM, Rosenblum K (2013) ApoE ε4 is associated with eIF2α phosphorylation and impaired learning in young mice. Neurobiol Aging 34:863–872. doi:10.1016/j.neurobiolaging.2012.06.020
Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM (2010) Aging of the innate immune system. Curr Opin Immunol 22:507–513. doi:10.1016/j.coi.2010.05.003
Shirato K, Imaizumi K (2014) Post-transcriptional suppression of lipopolysaccharide-stimulated inflammatory responses by macrophages in middle-aged mice: a possible role for eukaryotic initiation factor 2α. Int J Inflam 2014, Article ID: 292986.
Sun Y, Li H, Yang MF, Shu W, Sun MJ, Xu Y (2012) Effects of aging on endotoxin tolerance induced by lipopolysaccharides derived from Porphyromonas gingivalis and Escherichia coli. PLoS One 7:e39224. doi:10.1371/journal.pone.0039224
Tsaytler P, Harding HP, Ron D, Bertolotti A (2011) Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis. Science 332:91–94. doi:10.1126/science.1201396
Tsaytler P, Bertolotti A (2013) Exploiting the selectivity of protein phosphatase 1 for pharmacological intervention. FEBS J 280:766–770. doi:10.1111/j.1742-4658.2012.08535.x
Vega VL, De Cabo R, De Maio A (2004) Age and caloric restriction diets are confounding factors that modify the response to lipopolysaccharide by peritoneal macrophages in C57BL/6 mice. Shock 22:248–253
Weiskopf D, Weinberger B, Grubeck-Loebenstein B (2009) The aging of the immune system. Transpl Int 22:1041–1050. doi:10.1111/j.1432-2277.2009.00927.x
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer Japan
About this chapter
Cite this chapter
Shirato, K., Imaizumi, K. (2015). Mechanisms Underlying the Suppression of Inflammatory Responses in Peritoneal Macrophages of Middle-Aged Mice. In: Kanosue, K., Oshima, S., Cao, ZB., Oka, K. (eds) Physical Activity, Exercise, Sedentary Behavior and Health. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55333-5_16
Download citation
DOI: https://doi.org/10.1007/978-4-431-55333-5_16
Publisher Name: Springer, Tokyo
Print ISBN: 978-4-431-55332-8
Online ISBN: 978-4-431-55333-5
eBook Packages: MedicineMedicine (R0)