Role of very-late antigen-4 (VLA-4) in myelin basic protein-primed T cell contact-induced expression of proinflammatory cytokines in microglial cells.
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
Dasgupta
Subhajit
S
Department of Oral Biology, University of Nebraska Medical Center, Lincoln, Nebraska 68583-0740, USA.
Jana
Malabendu
M
Liu
Xiaojuan
X
Pahan
Kalipada
K
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D039041:Integrin alpha4beta1 / Q000502:physiology*; D007378:Interleukins / Q000096:biosynthesis; D008198:Lymph Nodes / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008815:Mice, Inbred Strains; D017628:Microglia / Q000276:immunology / Q000502:physiology*; D009169:Mycobacterium tuberculosis; D004676:Myelin Basic Protein / Q000502:physiology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014158:Transcription, Genetic
D022782:CCAAT-Enhancer-Binding Protein-beta; D016207:Cytokines; D039041:Integrin alpha4beta1; D007378:Interleukins; D004676:Myelin Basic Protein; D016328:NF-kappa B