TNF- -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 (TNF) on cytokine and chemokine production by human NPCs (>98% nestinand >90% A2B5-positive), obtained from 6to 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 timeand concentration-dependent manner. TNFtreatment 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-induced chemokine production and apoptosis by NPCs, as anti-TNFRI but not anti-TNFRII antibodies blocked the stimulatory effect. TNFtreatment induced p38 mitogenactivated protein kinase (MAPK) phosphorylation in NPCs, and SB202190, an inhibitor of p38 MAPK, blocked TNF-induced chemokine production. Thus, this study demonstrated that NPCs constitutively express receptors for TNF, which when activated, trigger via a p38 MAPK signaling pathway production of two chemokines, MCP-1/CCL2 and IP10/CXCL10, which are involved in infectious and inflammatory diseases of the brain. J. Leukoc. Biol. 78: 1233–1241; 2005.