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Defined inflammatory states in astrocyte cultures: correlation with susceptibility towards CD95‐driven apoptosis
Author(s) -
Falsig Jeppe,
Latta Markus,
Leist Marcel
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02144.x
Subject(s) - fas receptor , apoptosis , tumor necrosis factor alpha , fadd , death domain , fas ligand , nitric oxide , cytokine , astrocyte , microbiology and biotechnology , biology , caspase 8 , nitric oxide synthase , immunology , chemistry , programmed cell death , caspase , endocrinology , biochemistry , central nervous system
A complete cytokine mix (CCM) or its individual components tumour necrosis factor‐alpha (TNF‐α), interleukin‐1beta (IL‐1β) and interferon‐gamma (IFN‐γ) were used to switch resting murine astrocytes to reactive states. The transformation process was characterized by differential up‐regulation of interleukin‐6 (IL‐6), cyclooxygenase‐2 (COX‐2) and inducible nitric oxide synthetase (iNOS) mRNA and protein and a subsequent release of prostaglandin E2, nitric oxide (NO) and IL‐6. Both CD95L and anti‐CD95 antibodies triggered caspase activation followed by apoptotic death in fully pro‐inflammatory astrocytes, whereas resting cells were totally resistant. Two other death‐inducing ligands, TNF and TNF‐related apoptosis‐inducing ligand (TRAIL) did not induce apoptosis in reactive astrocytes. The switch in astrocyte sensitivity was accompanied by up‐regulation of caspase‐8 and CD95 as well as the capacity to recruit Fas‐associated death domain (FADD) to the activated death receptor complex. Neither CD95‐mediated death, nor other inflammatory parameters were affected by inhibition of iNOS or COX, respectively. Accordingly, IFN‐γ was absolutely essential for up‐regulation of iNOS, but not for the switch in apoptosis sensitivity. In contrast, p38 kinase activity was identified as an important controller of both the inflammatory reaction and apoptosis both in astrocytes stimulated with CCM and in glia exposed to TNF and IL‐1 only.