Role of very-late antigen-4 (VLA-4) in myelin basic protein-primed T cell contact-induced expression of proinflammatory cytokines in microglial cells

J Biol Chem. 2003 Jun 20;278(25):22424-31. doi: 10.1074/jbc.M301789200. Epub 2003 Apr 10.


The presence of neuroantigen-primed T cells recognizing self-myelin antigens within the CNS is necessary for the development of demyelinating autoimmune disease like multiple sclerosis. This study was undertaken to investigate the role of myelin basic protein (MBP)-primed T cells in the expression of proinflammatory cytokines in microglial cells. MBP-primed T cells alone induced specifically the microglial expression of interleukin (IL)-1beta, IL-1alpha tumor necrosis factor alpha, and IL-6, proinflammatory cytokines that are primarily involved in the pathogenesis of MS. This induction was primarily dependent on the contact between MBP-primed T cells and microglia. The activation of microglial NF-kappaB and CCAAT/enhancer-binding protein beta (C/EBPbeta) by MBP-primed T cell contact and inhibition of contact-mediated microglial expression of proinflammatory cytokines by dominant-negative mutants of p65 and C/EBPbeta suggest that MBP-primed T cells induce microglial expression of cytokines through the activation of NF-kappaB and C/EBPbeta. In addition, we show that MBP-primed T cells express very late antigen-4 (VLA-4), and functional blocking antibodies to alpha4 chain of VLA-4 (CD49d) inhibited the ability of MBP-primed T cells to induce microglial proinflammatory cytokines. Interestingly, the blocking of VLA-4 impaired the ability of MBP-primed T cells to induce microglial activation of only C/EBPbeta but not that of NF-kappaB. This study illustrates a novel role of VLA-4 in regulating neuroantigen-primed T cell-induced activation of microglia through C/EBPbeta

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Cells, Cultured
  • Coculture Techniques
  • Cytokines / biosynthesis*
  • Cytokines / immunology*
  • Female
  • Flow Cytometry
  • Integrin alpha4beta1 / physiology*
  • Interleukins / biosynthesis
  • Lymph Nodes / immunology
  • Lymph Nodes / microbiology
  • Mice
  • Mice, Inbred Strains
  • Microglia / immunology
  • Microglia / physiology*
  • Mycobacterium tuberculosis
  • Myelin Basic Protein / physiology*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • T-Lymphocytes / immunology*
  • Transcription, Genetic


  • CCAAT-Enhancer-Binding Protein-beta
  • Cytokines
  • Integrin alpha4beta1
  • Interleukins
  • Myelin Basic Protein
  • NF-kappa B