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(Journal of Leukocyte Biology. 2005;78:1233-1241.)
© 2005 by Society for Leukocyte Biology

TNF--induced chemokine production and apoptosis in human neural precursor cells

Wen S. Sheng^*,, Shuxian Hu^*,, Hsiao T. Ni, Tim N. Rowen^*,, James R. Lokensgard^*, and Phillip K. Peterson^*,,1

^* Neuroimmunology Laboratory, Minneapolis Medical Research Foundation, Minnesota;
Department of Medicine, University of Minnesota Medical School, Minneapolis; and
Stem Cell Group, R&D Systems, Inc., Minneapolis, Minnesota

¹ Correspondence: Department of Medicine, University of Minnesota Medical School, 420 Delaware Street, S.E., Minneapolis, MN 55455. E-mail: peter137{at}umn.edu

ABSTRACT

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% 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- 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--induced chemokine production and apoptosis by NPCs, as anti-TNFRI but not anti-TNFRII antibodies blocked the stimulatory effect. TNF- treatment induced p38 mitogen-activated 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 IP-10/CXCL10, which are involved in infectious and inflammatory diseases of the brain.

Key Words: cytokines • MCP-1 • IP-10 • CCL2 • CXCL10

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