TNF-α mediates SDF-1α-induced NF-κB activation and cytotoxic effects in primary astrocytes

Yulong Han, Tao He, DeRen Huang, Carlos A Pardo-Villamizar, Richard M. Ransohoff

Research output: Contribution to journalArticle

Abstract

Stromal-derived cell factor-1α (SDF-1α; CXCL12) and its receptor, CXCR4, are constitutively expressed on neuroepithelial cells and are believed to be involved in both development and pathological processes, such as AIDS-associated neurologic disorders. Here, we demonstrate that SDF-α activates NF-κB, stimulates production of chemokines and cytokines, and induces cell death in primary astrocytes, effects that depend on ongoing secretion of TNF-α. SDF-1α upregulated TNF-α mRNA and protein secretion, as well as TNF receptor 2 expression. TNF-α treatment mimicked SDF1α induction of NF-κB, IL-1α/β, and RANTES, as well as cell death; neutralizing antibodies against TNF-α opposed these responses. We also found that SDF-1α activated Erk1 and Erk2 (Erk1/2) MAPK in a biphasic fashion. Early Erk1/2 activation was stimulated directly by SDF-1α and late activation was mediated by TNF-α. PD98059 suppression of early Erk1/2 activation correlated with reduction of SDF-1α-induced TNF-α expression. Late Erk1/2 activation was involved in TNF-α-stimulated NF-κB activation and cytokine induction. SDF-1α was induced in reactive CXCR4-positive astrocytes near axotomized spinal cord motor neurons, consistent with autocrine SDF-1/CXCR4 signaling in these cells. We propose that these novel effects of SDF-1α are relevant to the pathogenic and developmental roles of SDF-1α in the CNS.

Original languageEnglish (US)
Pages (from-to)425-435
Number of pages11
JournalJournal of Clinical Investigation
Volume108
Issue number3
DOIs
StatePublished - 2001

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Astrocytes
Cell Death
Neuroepithelial Cells
Cytokines
CXCR4 Receptors
Chemokine CXCL12
Chemokine CCL5
Tumor Necrosis Factor Receptors
Motor Neurons
Pathologic Processes
Neutralizing Antibodies
Nervous System Diseases
Interleukin-1
Chemokines
Spinal Cord
Acquired Immunodeficiency Syndrome
Messenger RNA
Proteins
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

ASJC Scopus subject areas

  • Medicine(all)

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TNF-α mediates SDF-1α-induced NF-κB activation and cytotoxic effects in primary astrocytes. / Han, Yulong; He, Tao; Huang, DeRen; Pardo-Villamizar, Carlos A; Ransohoff, Richard M.

In: Journal of Clinical Investigation, Vol. 108, No. 3, 2001, p. 425-435.

Research output: Contribution to journalArticle

Han, Yulong ; He, Tao ; Huang, DeRen ; Pardo-Villamizar, Carlos A ; Ransohoff, Richard M. / TNF-α mediates SDF-1α-induced NF-κB activation and cytotoxic effects in primary astrocytes. In: Journal of Clinical Investigation. 2001 ; Vol. 108, No. 3. pp. 425-435.
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