Fas-induced expression of chemokines in human glioma cells: Involvement of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase

Fas transduces not only apoptotic signals through various pathways but also angiogenic and proinflammatory responses in vivo. Human glioma cells express Pas although sensitivity to Fas-mediated fell death is variable, suggesting that Pas may have functions other than apoptosis in these cells. In this study, we addressed alternative functions of Pas expressed on human gliomas by Pas ligation in three human glioma cell lines, CRT-MG, U373-MG, and U87-MG, and the in vivo expression of Pas and chemokines in human glioblastoma multiforme (GBM). Herein, we demonstrate that: (a) stimulation with agonistic anti-Pas monoclonal antibody CH-II and human recombinant soluble Pas ligand induces expression of the CC chemokine MCP-I and the CXC chemokine interleukin-8 by human glioma cell lines at the mRNA. and protein levels in a dose- and time-dependent manner; (b) selective pharmacological inhibitors of MEKI (U0126 and PD98059) and p38 mitogen-activated protein kinase (MAPK) (SB202190) suppress Pas-mediated chemokine expression in a dose-dependent manner; (c) Pas ligation on human glioma cells leads to activation of both extracellular signal-regulated kinases ERK1/ERK2 and p38 MAPK; and (d) GEM samples express higher levels of Pas compared with normal control brain, which correlates with increased interleukin 8 expression. These findings indicate that Pas ligation on human glioma cells leads to the selective induction of chemokine expression, which involves the ERK1/ERK2 and p38 MAPK signaling pathways. Therefore, the Fas-Fas ligand system in human brain tumors may be involved not only in apoptotic processes hut also in the provocation of angiogenic and proinflammatory responses.