TNF-alpha-induced chemokine production and apoptosis in human neural precursor cells.
Recent studies have shown that proinflammatory cytokines damage rodent neural precursor cells (NPCs), a source of self-renewing, multipotent cells that play an important role in the developing as well as adult brain. In this study, the effects of tumor necrosis factor alpha (TNF-alpha) on cytokine and chemokine production by human NPCs (>98% nestin- and >90% A2B5-positive), obtained from 6- to 8-week-old fetal brain specimens, were evaluated. NPCs stimulated with this proinflammatory cytokine were found to produce abundant amounts of the chemokines monocyte chemoattractant protein 1 (MCP-1)/CC chemokine ligand 2 (CCL2) and interferon-inducible protein 10 (IP-10)/CXC chemokine ligand 10 (CXCL10) in a time- and concentration-dependent manner. TNF-alpha treatment also induced NPC apoptosis. Receptors for TNF [TNFRI (p55) and TNFRII (p75)] mRNA were constitutively expressed on NPCs. However, only TNFRI was involved in TNF-alpha-induced chemokine production and apoptosis by NPCs, as anti-TNFRI but not anti-TNFRII antibodies blocked the stimulatory effect. TNF-alpha treatment induced p38 mitogen-activated protein kinase (MAPK) phosphorylation in NPCs, and SB202190, an inhibitor of p38 MAPK, blocked TNF-alpha-induced chemokine production. Thus, this study demonstrated that NPCs constitutively express receptors for TNF-alpha, which when activated, trigger via a p38 MAPK signaling pathway production of two chemokines, MCP-1/CCL2 and IP-10/CXCL10, which are involved in infectious and inflammatory diseases of the brain.
Sheng
Wen S
WS
Neuroimmunology Laboratory, Minneapolis Medical Research Foundation, and Department of Medicine, University of Minnesota Medical School, 420 Delaware Street, S.E., Minneapolis, MN 55455, USA.
Hu
Shuxian
S
Ni
Hsiao T
HT
Rowen
Tim N
TN
Lokensgard
James R
JR
Peterson
Phillip K
PK
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001921:Brain / Q000166:cytology / Q000276:immunology* / Q000503:physiopathology; D018932:Chemokine CCL2 / Q000276:immunology / Q000378:metabolism; D054357:Chemokine CXCL10; D018925:Chemokines / Q000276:immunology* / Q000378:metabolism; D019743:Chemokines, CXC / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004660:Encephalitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D009474:Neurons / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism
C111835:CCL2 protein, human; C114753:CXCL10 protein, human; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC; D016207:Cytokines; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; D064231:Nestin; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases