Abstract
BackgroundInterleukin (IL)-6 plays a pivotal role in a variety of CNS functions such as the induction and modulation of reactive astrogliosis, pathological inflammatory responses and neuroprotection. Tumor necrosis factor (TNF)-α induces IL-6 release from rat C6 glioma cells through the inhibitory kappa B (IκB)-nuclear factor kappa B (NFκB) pathway, p38 mitogen-activated protein (MAP) kinase and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK). The present study investigated the mechanism of TNF-α-induced IL-6 release in more detail than has previously been reported.MethodsCultured C6 cells were stimulated by TNF-α. IL-6 release from the cells was measured by an enzyme-linked immunosorbent assay, and the phosphorylation of IκB, NFκB, the MAP kinase superfamily, and signal transducer and activator of transcription (STAT)3 was analyzed by Western blotting. Levels of IL-6 mRNA in cells were evaluated by real-time reverse transcription-polymerase chain reaction.ResultsTNF-α significantly induced phosphorylation of NFκB at Ser 536 and Ser 468, but not at Ser 529 or Ser 276. Wedelolactone, an inhibitor of IκB kinase, suppressed both TNF-α-induced IκB phosphorylation and NFκB phosphorylation at Ser 536 and Ser 468. TNF-α-stimulated increases in IL-6 levels were suppressed by wedelolactone. TNF-α induced phosphorylation of STAT3. The Janus family of tyrosine kinase (JAK) inhibitor I, an inhibitor of JAK 1, 2 and 3, attenuated TNF-α-induced phosphorylation of STAT3 and significantly reduced TNF-α-stimulated IL-6 release. Apocynin, an inhibitor of NADPH oxidase that suppresses intracellular reactive oxygen species, significantly suppressed TNF-α-induced IL-6 release and mRNA expression. However, apocynin failed to affect the phosphorylation of IκB, NFκB, p38 MAP kinase, SAPK/JNK or STAT3.ConclusionThese results strongly suggest that TNF-α induces IL-6 synthesis through the JAK/STAT3 pathway in addition to p38 MAP kinase and SAPK/JNK in C6 glioma cells, and that phosphorylation of NFκB at Ser 536 and Ser 468, and NADPH oxidase are involved in TNF-α-stimulated IL-6 synthesis.
Highlights
Interleukin (IL)-6 plays a pivotal role in a variety of CNS functions such as the induction and modulation of reactive astrogliosis, pathological inflammatory responses and neuroprotection
These results strongly suggest that Tumor necrosis factor (TNF)-a induces IL-6 synthesis through the Janus family of tyrosine kinase (JAK)/STAT3 pathway in addition to p38 mitogen-activated protein (MAP) kinase and stress-activated protein kinase (SAPK)/Jun N-terminal kinase (JNK) in C6 glioma cells, and that phosphorylation of nuclear factor kappa B (NFB) at Ser 536 and Ser 468, and NADPH oxidase are involved in TNF-a-stimulated IL-6 synthesis
The present study investigated the phosphorylation of specific residues of NFB is association with TNF-a-stimulated IL-6 synthesis in C6 glioma cells
Summary
Interleukin (IL)-6 plays a pivotal role in a variety of CNS functions such as the induction and modulation of reactive astrogliosis, pathological inflammatory responses and neuroprotection. Tumor necrosis factor (TNF)-a induces IL-6 release from rat C6 glioma cells through the inhibitory kappa B (IB)-nuclear factor kappa B (NFB) pathway, p38 mitogen-activated protein (MAP) kinase and stress-activated protein kinase (SAPK)/ c-Jun N-terminal kinase (JNK). NFB, p38 mitogen-activated protein (MAP) kinase and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) in rat C6 glioma cells [4]. The activation of the JAK-STAT pathway leads to a rapid signaling from the cell surface to the nucleus [6]. JAK proteins are phosphorylated when cytokines bind to specific receptors, and subsequently activate STATs. The activated STATs translocate to the nucleus and transmit the signals, where they bind to specific consensus sequences, thereby triggering gene transcription [6]. The precise role of the JAK-STAT pathway in glial cells remains to be elucidated
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