Abstract
Endotoxin tolerance is characterized by a decreased production of proinflammatory cytokines by cultured leukocytes in response to lipopolysaccharide (LPS) following a first exposure to the same stimulus. Gamma interferon (IFNgamma) and granulocyte/monocyte colony-stimulating factor (GM-CSF) are immunostimulatory cytokines that prime monocytes and prevent endotoxin tolerance. In this study, we show that the deactivating effects of LPS, as well as the priming effects of IFNgamma and GM-CSF or their capacity to restore tumor necrosis factor (TNF) production by LPS-tolerized human monocytes are independent of the modulation of TLR2, TLR4, or MD-2. In monocytes pretreated with IFNgamma or GM-CSF, interleukin-1 receptor-associated kinase (IRAK) expression is up-regulated. After LPS stimulation, an increased IRAK kinase activity, a higher MyD88/IRAK association, and a stronger NF-kappaB activation are observed. In contrast, in LPS-tolerized monocytes, IRAK expression and kinase activity, IRAK/MyD88 association, and NF-kappaB activation are inhibited. Furthermore, the prevention of tolerance by IFNgamma and GM-CSF was independent of IRAK kinase activity. Our results suggest that these cytokines prevent endotoxin tolerance induced by low but not by high doses of LPS by inhibiting IRAK degradation and by promoting its association with MyD88 after a second LPS stimulation, which in turn leads to NF-kappaB activation and TNF production.
Highlights
IL-12 [2,3,4]; this is not the case for IL-1ra [3]
We show that the deactivating effects of LPS, as well as the priming effects of IFN␥ and granulocyte/monocyte colonystimulating factor (GM-CSF) or their capacity to restore tumor necrosis factor (TNF) production by LPS-tolerized human monocytes are independent of the modulation of TLR2, TLR4, or MD-2
We studied the expression of TLR4, TLR2, and MD-2 mRNA by Reverse transcription (RT)-PCR, as well as that of TLR4 on the surface of monocytes after exposure to low or high doses of LPS, IFN␥, or GM-CSF
Summary
A defect in the activation of transcription factor NF-B has been reported [5], the precise mechanism leading to this hyporeactivity remains unknown This deactivation found in leukocytes from septic patients resembles the phenomenon called endotoxin tolerance. Endotoxin tolerance is thought to be an adaptive response that tends to limit the overwhelming inflammation that occurs during bacterial infection, but it may favor subsequent infections in survivors of septic shock It is associated with a decreased production of proinflammatory cytokines and with changes in the cellular levels and composition of NF-B. It has been reported that TLRs and IL-1R share several signaling molecules including adaptor protein MyD88, interleukin-1 receptor-associated kinase (IRAK), and TNF receptor-activated factor 6 (TRAF6) [14]. IFN␥ and GM-CSF can prevent LPS tolerance induced in vivo [28]
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