Fas ligation and tumor necrosis factor α activation of murine astrocytes promote heat shock factor-1 activation and heat shock protein expression leading to chemokine induction and cell survival.
Death-inducing ligands tumor necrosis factor alpha (TNFα) and Fas ligand (FasL) do not kill cultured astrocytes; instead they induce a variety of chemokines including macrophage-inflammatory protein-1α/CC chemokine ligand 3 (CCL3), monocyte chemoattractant protein-1 (CC CCL-2), macrophage-inflammatory protein-2/CXC chemokine ligand 2 (CXCL2, a murine homologue of interleukin 8), and interferon-induced protein of 10 kDa (CXCL10). Induction is enhanced by protein synthesis inhibition suggesting the existence of endogenous inhibitors. ERK, NF-κB, heat shock factor-1 (HSF-1) and heat shock proteins were examined for their possible roles in signal transduction. Inhibition of ERK activation by PD98059 partially inhibited expression of all but FasL-induced CXCL10. Although inhibition of NF-κB DNA binding inhibited chemokine induction, PD98059 did not inhibit TNFα-induced NF-κB DNA binding suggesting that ERK serves an NF-κB-independent pathway. Heat shock itself induced astrocytic chemokine expression; both TNFα and FasL induced HSF-1 DNA binding and Hsp72 production; and Hsp72-induced chemokine expression. Inhibition of either HSF-1 binding with quercetin or heat shock protein synthesis with KNK437 compromised chemokine induction without compromising cell survival. These data suggest that the induction of heat shock proteins via HSF-1 contribute to the TNFα- and FasL-induced expression of chemokines in astrocytes.
Federated Department of Biological Sciences, New Jersey Institute of Technology/Rutgers University, Newark, New Jersey 07102, USA.
Kuicheon
K
Choi
Li
L
Ni
G Miller
GM
Jonakait
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001253:Astrocytes / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D053222:Fas Ligand Protein / Q000378:metabolism* / Q000502:physiology; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000502:physiology; D019014:fas Receptor / Q000378:metabolism
D018925:Chemokines; D004268:DNA-Binding Proteins; D053222:Fas Ligand Protein; C491899:Fas protein, mouse; C505658:Fasl protein, mouse; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C490017:Hsf1 protein, mouse; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor