Mechanisms of interleukin-1beta-induced GDNF release from rat glioma cells.
Glial cell line-derived neurotrophic factor (GDNF) is highly expressed both in neurons and astrocytes in injured tissues. Astrocytes support neurons by releasing neurotrophic factors including GDNF. It has been reported that various agents including cytokines such as interleukin (IL)-1beta induce GDNF mRNA expression and the release in astrocytes. However, the mechanism behind the GDNF synthesis and release remains unclear. Herein, we investigated the mechanisms of the IL-1beta-induced GDNF release from rat C6 glioma cells. IL-1beta time dependently stimulated GDNF release from C6 cells. IL-1beta induced the phosphorylation of inhibitor kappa B (IkappaB), p38 mitogen-activated protein (MAP) kinase, p44/p42 MAP kinase, stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and signal transducer and activator of transcription (STAT) 3. The IL-1beta-stimulated levels of GDNF were suppressed by wedelolactone, an inhibitor of IkappaB kinase, SB203580, an inhibitor of p38 MAP kinase, PD98059, an inhibitor of MAP kinase kinase 1/2 or Janus family of tyrosine kinase (JAK) inhibitor I, an inhibitor of upstream kinase of STAT3. On the contrary, SP600125, an inhibitor of SAPK/JNK, failed to reduce the IL-1beta-effect. These results strongly suggest that IL-1beta stimulates GDNF release through the pathways of IkappaB-nuclear factor kappa B, p38 MAP kinase, p44/p42 MAP kinase and JAK-STAT3, but not through the SAPK/JNK pathway in glioma cells.
Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan. kumiko-t@m2.gyao.ne.jp
Kumiko
K
Tanabe
Kazumi
K
Nishimura
Shuji
S
Dohi
Osamu
O
Kozawa
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000187:drug effects / Q000378:metabolism*; D005910:Glioma / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
D004791:Enzyme Inhibitors; D051100:Glial Cell Line-Derived Neurotrophic Factor; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases