Glucocorticoids attenuate interleukin-6-induced c-Fos and Egr1 expression and impair neuritogenesis in PC12 cells

Interleukin-6 (IL-6) is a cytokine primarily known for immune regulation. There is also growing evidence that IL-6 triggers neurogenesis and impacts neural development, both life-long occurring processes that can be impaired by early-life and adult stress. Stress induces the release of glucocorticoids by activation of the hypothalamic-pituitary-adrenal (HPA) axis. On the cellular level, glucocorticoids act via the ubiquitously expressed glucocorticoid receptor. Thus, we aimed to elucidate whether glucocorticoids affect IL-6-induced neural development. Here, we show that IL-6 signalling induces neurite outgrowth in adrenal pheochromocytoma PC12 cells in a mitogen-activated protein kinase (MAPK) pathway-dependent manner, since neurite outgrowth was diminished upon Mek-inhibitor treatment. Using quantitative biochemical approaches, such as qRT-PCR analysis of Hyper-IL-6 treated PC12 cells, we show that neurite outgrowth induced by IL-6 signalling is accompanied by early and transient MAPK-dependent mRNA expression of immediate early genes coding for proteins such as early growth response protein 1 (Egr1) and c-Fos. This correlates with reduced proliferation and prolonged G0/G1 cell cycle arrest as determined by monitoring the cellular DNA content using flow cytometry. These results indicate for IL-6 signalling-induced neural differentiation. Interestingly, the glucocorticoid Dexamethasone impairs early IL-6 signalling-induced mRNA expression of c-Fos and Egr1 and restrains neurite outgrowth. Impaired Egr1 and c-Fos expression in neural development is implicated in the aetiology of neuropathologies. Thus, it appears likely that stress-induced release of glucocorticoids, as well as therapeutically administered glucocorticoids, contribute to the development of neuropathologies by reducing the expression of Egr1 and c-Fos, and by restraining IL-6-dependent neural differentiation.