Interleukin-1-induced interleukin-6 synthesis is mediated by the neutral sphingomyelinase/Src kinase pathway in neurones.

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  • Author(s): Tsakiri N;Tsakiri N; Kimber I; Rothwell NJ; Pinteaux E
  • Source:
    British journal of pharmacology [Br J Pharmacol] 2008 Feb; Vol. 153 (4), pp. 775-83. Date of Electronic Publication: 2007 Dec 03.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Wiley Country of Publication: England NLM ID: 7502536 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0007-1188 (Print) Linking ISSN: 00071188 NLM ISO Abbreviation: Br J Pharmacol Subsets: MEDLINE
    • Publication Information:
      Publication: London : Wiley
      Original Publication: London, Macmillian Journals Ltd.
    • Subject Terms:
      Signal Transduction*; Cerebral Cortex/*metabolism ; Interleukin-1beta/*metabolism ; Interleukin-6/*biosynthesis ; Neurons/*metabolism ; Sphingomyelin Phosphodiesterase/*metabolism ; src-Family Kinases/*metabolism; Animals ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Cerebral Cortex/embryology ; Cerebral Cortex/enzymology ; Cyclic AMP Response Element-Binding Protein/metabolism ; Enzyme Activation ; Mice ; Mice, Inbred C57BL ; Neurons/enzymology ; Phosphorylation ; Receptors, Interleukin-1 Type I/metabolism ; Receptors, N-Methyl-D-Aspartate/metabolism ; Recombinant Proteins/metabolism
    • Abstract:
      Background and Purpose: Interleukin (IL)-1 is a key mediator of inflammatory and host defence responses and its effects in the brain are mediated primarily via effects on glia. IL-1 induces release of inflammatory mediators such as IL-6 from glia via the type-1 receptor (IL-1R1) and established signalling mechanisms including mitogen-activated protein kinases and nuclear factor kappa-B. IL-1 also modifies physiological functions via actions on neurones, through activation of the neutral sphingomyelinase (nSMase)/Src kinase signalling pathway, although the mechanism of IL-1-induced IL-6 synthesis in neurones remains unknown.
      Experimental Approach: Primary mouse neuronal cell cultures, ELISA, Western blot and immunocytochemistry techniques were used.
      Key Results: We show here that IL-1beta induces the synthesis of IL-6 in primary mouse neuronal cultures, and this is dependent on the activation of IL-1R1, nSMase and Src kinase. We demonstrate that IL-1beta-induced Src kinase activation triggers the phosphorylation of the NMDA receptor NR2B subunit, leading to activation of Ca(2+)/calmodulin-dependent protein kinase II (CamKII) and the nuclear transcription factor CREB. We also show that NR2B, CamKII and CREB are essential signalling elements involved in IL-1beta-induced IL-6 synthesis in neurones.
      Conclusions and Implications: These results demonstrate that IL-1 interacts with the same receptors on neurones and glia to elicit IL-6 release, but does so via distinct signalling pathways. The mechanism by which IL-1beta induces IL-6 synthesis in neurones could be critical in both physiological and pathophysiological actions of IL-1beta, and may provide a new therapeutic target for the treatment of acute CNS injury.
    • References:
      Br J Pharmacol. 2002 May;136(2):312-20. (PMID: 12010781)
      Mol Cell Neurosci. 2008 Jan;37(1):110-8. (PMID: 17933551)
      J Neurosci. 1999 Dec 15;19(24):10923-30. (PMID: 10594073)
      Acta Pharmacol Sin. 2000 Aug;21(8):695-700. (PMID: 11501177)
      J Neuroimmunol. 2003 Nov;144(1-2):61-7. (PMID: 14597099)
      Neurobiol Aging. 1997 May-Jun;18(3):343-8. (PMID: 9263201)
      Clin Sci (Lond). 2007 Jan;112(1):1-25. (PMID: 17132137)
      Nat Rev Neurosci. 2001 Oct;2(10):734-44. (PMID: 11584311)
      J Neurosci. 2004 Mar 17;24(11):2837-45. (PMID: 15028778)
      J Neurosci. 1995 Jul;15(7 Pt 2):5130-8. (PMID: 7623140)
      J Neurochem. 2006 Sep;98(5):1379-89. (PMID: 16771830)
      J Neurosci. 1988 Feb;8(2):709-14. (PMID: 3257519)
      Ann N Y Acad Sci. 1998 Sep 29;856:132-8. (PMID: 9917873)
      Eur J Neurosci. 2000 Oct;12(10):3505-20. (PMID: 11029620)
      Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11534-9. (PMID: 11016948)
      J Biol Chem. 2006 Oct 6;281(40):30212-22. (PMID: 16887807)
      J Neuroimmunol. 1989 Jul;23(2):109-16. (PMID: 2656753)
      J Neurosci. 2005 Aug 31;25(35):8000-9. (PMID: 16135757)
      Stroke. 1995 Apr;26(4):676-80; discussion 681. (PMID: 7709417)
      Eur J Pharmacol. 1990 Jun 8;181(3):323-6. (PMID: 2166677)
      Brain Behav Immun. 2003 Jun;17(3):152-7. (PMID: 12706413)
      Am J Physiol. 1996 Jul;271(1 Pt 2):R101-8. (PMID: 8760209)
      Trends Neurosci. 2001 Aug;24(8):450-5. (PMID: 11476884)
      J Biol Chem. 2001 Dec 7;276(49):45564-72. (PMID: 11581275)
      J Cereb Blood Flow Metab. 2000 Jun;20(6):956-66. (PMID: 10894179)
      Regul Pept. 1992 Apr 29;39(1):1-7. (PMID: 1579655)
      J Neurosci Res. 2004 Oct 15;78(2):151-6. (PMID: 15378607)
      Neuroreport. 2000 Aug 3;11(11):2565-9. (PMID: 10943723)
      J Neuroimmunol. 1995 Dec 31;63(2):113-23. (PMID: 8550808)
      J Neurosci. 2000 Dec 1;20(23):8637-42. (PMID: 11102468)
      Neurosci Biobehav Rev. 2001 Jan;25(1):29-41. (PMID: 11166076)
      Neuroscience. 1999;89(4):1051-66. (PMID: 10362294)
      J Neurosci. 2001 Sep 15;21(18):7046-52. (PMID: 11549714)
      J Neurosci. 2002 Jul 15;22(14):6071-82. (PMID: 12122068)
      J Neurosci. 2003 Sep 24;23(25):8692-700. (PMID: 14507968)
      J Physiol. 2003 Jul 1;550(Pt 1):113-22. (PMID: 12879863)
      Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2904-8. (PMID: 16477014)
      Nat Med. 2001 Feb;7(2):222-7. (PMID: 11175854)
      Stroke. 2007 May;38(5):1621-5. (PMID: 17395859)
      Glia. 2005 Jan 15;49(2):161-76. (PMID: 15472994)
      Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7778-83. (PMID: 9636227)
      Mol Cell Neurosci. 2002 Jul;20(3):489-502. (PMID: 12139924)
      Philos Trans R Soc Lond B Biol Sci. 2003 Oct 29;358(1438):1669-77. (PMID: 14561325)
      Br J Pharmacol. 2002 Feb;135(4):1069-77. (PMID: 11861336)
      Nat Rev Neurosci. 2004 Apr;5(4):317-28. (PMID: 15034556)
      Respir Physiol Neurobiol. 2007 Aug 1;157(2-3):187-95. (PMID: 17321804)
    • Grant Information:
      G9219675 United Kingdom MRC_ Medical Research Council
    • Accession Number:
      0 (Creb1 protein, mouse)
      0 (Cyclic AMP Response Element-Binding Protein)
      0 (Interleukin-1beta)
      0 (Interleukin-6)
      0 (NR2B NMDA receptor)
      0 (Receptors, Interleukin-1 Type I)
      0 (Receptors, N-Methyl-D-Aspartate)
      0 (Recombinant Proteins)
      EC 2.7.10.2 (src-Family Kinases)
      EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
      EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
    • Publication Date:
      Date Created: 20071207 Date Completed: 20080514 Latest Revision: 20211027
    • Publication Date:
      20231215
    • Accession Number:
      PMC2259207
    • Accession Number:
      10.1038/sj.bjp.0707610
    • Accession Number:
      18059318