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Signaling Mechanisms Involved in the Activation of Arachidonic Acid Metabolism in Human Astrocytoma Cells by Tumor Necrosis Factor‐α
Author(s) -
Hernández Marita,
Bayón Yolanda,
Crespo Mariano Sánchez,
Nieto María Luisa
Publication year - 1999
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 - 10.1046/j.1471-4159.1999.0731641.x
Subject(s) - kinase , biology , tumor necrosis factor alpha , p38 mitogen activated protein kinases , protein kinase a , mitogen activated protein kinase , map kinase kinase kinase , arachidonic acid , signal transduction , mitogen activated protein kinase kinase , microbiology and biotechnology , endocrinology , biochemistry , enzyme
: Tumor necrosis factor‐α (TNF‐α) is a cytokine that elicits cell responses by activating the mitogen‐activated protein kinase (MAP kinase) cascade and transcription factors such as nuclear factor‐ k B (NF‐ k B). As these elements play a central role in the mechanisms of signaling involved in the activation of cytosolic phospholipase A 2 (cPLA 2 ) and cyclooxygenase‐2 (COX‐2), the effect of TNF‐α on arachidonate (AA) metabolism in 1321N1 astrocytoma cells was assayed. TNF‐α produced a phosphorylation of cPLA 2 , which was preceded by an activation of both c‐Jun N‐terminal kinase (JNK) and p38‐MAP kinase, and this was associated with the release of [ 3 H]AA. In contrast, TNF‐α did not activate the extracellular signal‐regulated kinase (MAP kinase) p42, nor did it elicit a mitogenic response. Analysis of [ 3 H]AA metabolites by reverse‐phase HPLC showed that all of the [ 3 H]AA released during the first hour after TNF‐α addition eluted as authentic AA, whereas in samples obtained at 24 h after addition of TNF‐α, 25% of the [ 3 H]AA had been converted into COX products as compared with only 9% in control cells. In keeping with these findings, TNF‐α produced an increase of COX‐2 expression, as judged from both RT‐PCR studies and immunoblot of COX‐2 protein, and a long‐lasting activation of NF‐ k B. These data show that TNF‐α produces in astrocytoma cells an early activation of both p38‐MAP kinase and JNK, which is followed by the phosphorylation of cPLA 2 and the release of AA. On the other hand, the activation of NF‐ k B may explain the induction of the expression of COX‐2 and the delayed generation of prostanoids.