TNF-alpha mediates SDF-1 alpha-induced NF-kappa B 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 activates NF-kappa B, stimulates production of chemokines and cytokines, and induces cell death in primary astrocytes, 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-kappa B, 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-kappa B 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.
Han
Y
Y
Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
He
T
T
Huang
D R
DR
Pardo
C A
CA
Ransohoff
R M
RM
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000235:genetics; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D020672:I-kappa B Proteins; D007375:Interleukin-1 / Q000235:genetics; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
D015703:Antigens, CD; D018946:Chemokine CCL5; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D004268:DNA-Binding Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D020928:Mitogen-Activated Protein Kinases