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
View: Text | PDF
Article

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

×

Figure 3

Options: View larger image (or click on image) Download as PowerPoint
SDF-1α induces expression of TNF-α, IL-1, RANTES, and TNFR2 in primary a...
SDF-1α induces expression of TNF-α, IL-1, RANTES, and TNFR2 in primary astrocytes. (a) SDF-1α induces TNF-α, IL-1, and RANTES mRNA expression in primary astrocytes. Astrocytes were incubated with or without SDF-1α for the indicated periods of time. RNA was prepared and analyzed by RPA using cytokine and chemokine probe sets. Unprotected probe bands are indicated with arrows on the right and protected bands are shown with arrows on the left. Data represent four experiments. (b) SDF-1α stimulates TNF-α protein expression in primary astrocytes. Astrocytes in 12-well plates were incubated with or without SDF-1α for the indicated periods of time. TNF-α concentration in the culture medium was quantitated using the Mu TNF-α Cytokine Direct ELISA Kit. TNF-α concentration obtained from triplicate wells is shown as the mean ± SD. Data represent three independent experiments. (c) SDF-1α induces TNFR2 expression in primary astrocytes. Astrocytes were incubated with or without SDF-1α for the indicated periods of time. RNA was prepared and analyzed by RPA. Unprotected probe bands are indicated with arrows on the left and protected bands are shown with arrows on the right. Data represent three experiments.