β‐Naphthoflavone disturbs astrocytic differentiation of C6 glioma cells by inhibiting autocrine interleukin‐6

Abstract

Regulation of astrocyte differentiation is a key process in the development of the central nervous system (CNS), and disturbance of the differentiation can lead to brain system dysfunction. Here we show that b-naphthoflavone (bNF), an agonist of the aryl hydrocarbon receptor (AhR), disturbed the cAMP-induced astrocytic differentiation of C6 glioma by inhibiting autocrine interleukin-6 (IL-6). Treatment of cells with bNF reduced the induction of an astrocyte marker glial fibrillary acidic protein (GFAP). This was caused by the inactivation of its upstream transcription factor signal transducer and activator of transcription 3 (STAT3) by bNF. In addition, bNF attenuated the induction of the IL-6 gene, which leads to the activation of STAT3. Most importantly, the inhibitory effect of bNF on GFAP promoter activity was recovered by the addition of recombinant IL-6. Taken together, these results indicate that the inhibitory effect of bNF on IL-6 induction suppresses STAT3 activation. These processes subsequently lead to the attenuation of GFAP induction.

Activation of a pro‐survival pathway IL‐6/JAK2/STAT3 contributes to glial fibrillary acidic protein induction during the cholera toxin‐induced differentiation of C6 malignant glioma cells

“…Furthermore, it is well established that GFAP is not only a reliable marker for gliogenesis but also works as a tumor suppressor gene in malignant glioma pathogenesis (Duffy et al., 1982; Rutka et al., 1994; Rutka and Smith, 1993). Therefore, our findings support those previous reports demonstrating that proinflammatory cytokines might work as potential differentiation‐supporting agents against malignant gliomas (Koch et al., 2007; Slegers and Joniau, 1996; Takanaga et al., 2004).…”

“…Interleukin-6 (IL-6)-type cytokines are major regulators of inflammation and thereby contribute to the neuropathology and pathophysiology associated with inflammation of the central nervous system (CNS) (Koch et al, 2007). Furthermore, it is well established that GFAP is not only a reliable marker for gliogenesis but also works as a tumor suppressor gene in malignant glioma pathogenesis (Duffy et al, 1982;Rutka et al, 1994;Rutka and Smith, 1993).Therefore, our findings support those previous reports demonstrating that proinflammatory cytokines might work as potential differentiation-supporting agents against malignant gliomas (Koch et al, 2007;Slegers and Joniau, 1996;Takanaga et al, 2004).…”

Aryl Hydrocarbon Receptor Promotes IL-10 Expression in Inflammatory Macrophages Through Src-STAT3 Signaling Pathway

“…Previous evidences showed that STAT3 activation regulated downstream genes by AhR ligands including TCDD ( 45 ), indoxyl sulfate ( 46 ), and β-naphthoflavone ( 47 ). However, the current results showed that ligand-independent activation of AhR could efficiently mobilize LPS-stimulated STAT3.…”

Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound

“…33 In another study, inhibition of IL-6 by the AhR agonist ␤-naphthoflavone in C6 glioma cells was demonstrated, leading to a block in astrocyte differentiation for which IL-6 is an important autocrine factor. 34 Given the complex biology of the AhR, several scenarios can be envisioned to explain the mode of action of VAF347 on DC to inhibit IL-6 production. One possibility is the presence of negatively acting AhR binding sites in the IL-6 promoter.…”