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

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-1α 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 SDF-1α 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.

Authors

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

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Figure 8

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Schematic representation of the signaling pathways activated by SDF-1α i...
Schematic representation of the signaling pathways activated by SDF-1α in primary astrocytes. SDF-1α binding to CXCR4 elicits intracellular signaling including the Erk1/2 MAPK cascade, which initiates activation of TNF-α transcription. TNF-α protein is then synthesized and secreted to the extracellular space (or medium), where it binds to its receptors. TNF-α engagement with its receptors initiates signals leading to cell death and activation of NF-κB and Erk1/2 MAPK. Activated NF-κB and Erk1/2 MAPK in turn translocate to the nucleus and activate IL-1 and RANTES expression.