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

Stromal-derived cell factor-1 alpha (SDF-1 alpha; 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-1 alpha astrocytes, NF-kappaB effects that depend on ongoing secretion of TNF-alpha. SDF-1 alpha upregulated TNF-alpha mRNA and protein secretion, as well as TNF receptor 2 expression. TNF-alpha treatment mimicked SDF-1 alpha induction of NF-kappaB, IL-1 alpha/beta, and RANTES, as well as cell death; neutralizing antibodies against TNF-alpha opposed these responses. We also found that SDF-1 alpha activated Erk1 and Erk2 (Erk1/2) MAPK in a biphasic fashion. Early Erk1/2 activation was stimulated directly by SDF-1 alpha and late activation was mediated by TNF-alpha. PD98059 suppression of early Erk1/2 activation correlated with reduction of SDF-1 alpha -induced TNF-alpha expression. Late Erk1/2 activation was involved in TNF-alpha -stimulated NF-kappaB-activation and cytokine induction. SDF-1 alpha 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-1 alpha are relevant to the pathogenic and developmental roles of SDF-1 alpha in the CNS.