IL-1β, an immediate early protein secreted by activated microglia, induces iNOS/NO in C6 astrocytoma cells through p38 MAPK and NF-κB pathways

被引:95
作者
Kim, Yun-Jung
Hwang, So-Young
Oh, Eok-Soo
Oh, Seikwan
Han, Inn-Oc
机构
[1] Inha Univ, Dept Physiol & Biophys, Coll Med, Inchon 402751, South Korea
[2] Inha Univ, Ctr Adv Med Educ, Coll Med, Project BK21, Inchon 402751, South Korea
[3] Ewha Womans Univ, Dept Neurosci, Med Res Inst, Seoul, South Korea
[4] Ewha Womans Univ, Dept Life Sci, Div Mol Life Sci, Seoul, South Korea
[5] Ewha Womans Univ, Ctr Cell Signaling Res, Seoul, South Korea
关键词
iNOS; microglia; astrocytoma; IL-1; beta;
D O I
10.1002/jnr.21011
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
In the present study we sought to examine cell-cell interactions by investigating the effects of factors released by stimulated microglia on inducible nitric oxide (NO) synthase (NOS) induction in astrocytoma cells. After examining the temporal profiles of proinflammatory molecules induced by lipopolysaccharide (LPS) stimulation in BV2 microglial cells, NOS and IL-1 beta were observed to be the first immediate-response molecules. Removal of LPS after 3 hr stimulation abrogated NO release, whereas a full induction of IL-1 beta was retained in BV2 cells. We observed consistently that conditioned medium (CM) from activated microglia resulted in the induction of NOS in C6 cells, and IL-1 beta was shown to be a key regulator of NOS induction. An IL-1 beta-neutralizing antibody diminished NO induction. Incubation with recombinant IL-1 beta stimulated NO release to a lesser extent compared to microglial CM; co-treatment of LPS and IL-1 beta had a potent, synergistic effect on NO release from C6 cells. Transient transfection with MEK kinase 1 (MEKK1) or nuclear factor-kappa B (NF-kappa B) expression plasmids induced NOSE and IL-1 beta further enhanced the MEKK1 response. Furthermore, IL-1 beta-mediated NO release from C6 cells was significantly suppressed by inhibition of p38 mitogen activated protein kinase (MAPK) or NF-kappa B by specific chemical inhibitors. Both IL-1 beta and MEKK1 stimulated p38 and JNK MAPKs, as well as the NF-kappa B pathway, to induce NOS in C6 cells. Microglia may represent an anti-tumor response in the central nervous system, which is potentiated by the local secretion of immunomodulatory factors that in turn affects astrocytoma (glioma) cells. A better understanding of microglia-glioma or microglia-astrocyte interactions will help in the design of novel immune-based therapies for brain tumors or neuronal diseases. (c) 2006 Wiley-Liss, Inc.
引用
收藏
页码:1037 / 1046
页数:10
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