Intensive Care Medicine

, Volume 38, Issue 8, pp 1392–1399 | Cite as

Temperature- and time-dependent changes in TLR2-activated microglial NF-κB activity and concentrations of inflammatory and anti-inflammatory factors

  • Tomohiro Matsui
  • Moe Tasaki
  • Takahiro Yoshioka
  • Yukari Motoki
  • Hidehiro Tsuneoka
  • Junzo Nojima



Therapeutic hypothermia protects neurons following injury to the central nervous system (CNS). Microglia express toll-like receptors (TLRs) that play significant roles in pathological processes in sterile CNS injury. We have examined the effects of culture temperature on the TLR2-activated microglial production of cytokines and nitric oxide (NO), which are known to be associated with CNS damage, and the possible involvement of nuclear factor-κB (NF-κB) activation underlying such effects.


Rat microglia were cultured with a selective TLR2 agonist, Pam3CSK4, under hypothermic, normothermic, and hyperthermic conditions, and with Pam3CSK4 in the presence of a NF-κB activation inhibitor at 37 °C. Cytokine and NO levels and NF-κB p65 activation were measured.


The production of tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), and NO and the activation of NF-κB p65 were reduced by hypothermia, but augmented by hyperthermia at 3–6, 24–48, 48, and 0.5 h, post-treatment initiation, respectively. Pharmacological inhibition of NF-κB activation impaired the Pam3CSK4-induced TNF-α, IL-10, and NO production.


In TLR2-activated microglia, hypothermia reduced, while hyperthermia increased, the early activation of NF-κB and the subsequent NF-κB-mediated production of TNF-α, IL-10, and NO in a time-dependent manner, suggesting that attenuation of these factors via suppression of NF-κB in microglia is one possible neuroprotective mechanism of therapeutic hypothermia. Moreover, temperature-dependent changes in microglial TNF-α production during the early phase and IL-10 and NO production during the late phase indicate that these factors might be useful as clinical markers to monitor hypothermia-related neuronal protection and hyperthermia-related neuronal injury.


Microglia Hypothermia Hyperthermia Toll-like receptor 2 Nuclear factor-κB Cytokines 



This research was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Grant-in-Aid for Young Scientists (B), No. 22791435 to T.M.


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Copyright information

© Copyright jointly held by Springer and ESICM 2012

Authors and Affiliations

  • Tomohiro Matsui
    • 1
  • Moe Tasaki
    • 1
  • Takahiro Yoshioka
    • 1
  • Yukari Motoki
    • 1
  • Hidehiro Tsuneoka
    • 1
  • Junzo Nojima
    • 1
  1. 1.Department of Laboratory SciencesYamaguchi University Graduate School of MedicineUbeJapan

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