Endoplasmic reticulum stress differentially modulates the IL-6 family of cytokines in murine astrocytes and macrophages

In many diseases, misfolded proteins accumulate within the endoplasmic reticulum (ER), leading to ER stress. In response, the cell initiates the unfolded protein response (UPR) to reestablish homeostasis. Additionally, in response to ER stress, various cell types mount an inflammatory response involving interleukin (IL)-6. While IL-6 has been widely studied, the impact of ER stress on other members of the IL-6 cytokine family, including oncostatin (OSM), IL-11, ciliary neurotrophic factor (CNTF), and leukemia inhibitor factor (LIF) remains to be elucidated. Here, we have examined the expression of the IL-6 family cytokines in response to pharmacologically-induced ER stress in astrocytes and macrophages, which express IL-6 in response to ER stress through different mechanisms. Our findings indicate that, in astrocytes, ER stress regulates mRNA expression of the IL-6 family of cytokines that is, in part, mediated by PKR-like ER kinase (PERK) and Janus kinase (JAK) 1. Additionally, in astrocytes, CNTF expression was suppressed through a PERK-dependent mechanism. Macrophages display a different profile of expression of the IL-6 family that is largely independent of PERK. However, IL-6 expression in macrophages was dependent on JAK signaling. Overall, this study demonstrates the cell-specific and differential mechanisms controlling expression of the IL-6 family of cytokines in response to ER stress.

The study of the remyelinating effect of leukemia-inhibitor factor and melatonin on the toxic cuprizone model of demyelination of murine cerebellar cells culture in vitro

The cuprizone model of toxic demyelination in vitro is widely used to study the of de- and remyelination in the CNS, as well as to address the issues of finding potential compounds that affect myelination of neuron axons.The aim of the study was to investigate the role of recombinant human leukemia inhibitory factor (rhLIF) and melatonin in remyelination, using the cuprizone demyelination model in vitro.Methods. To study the features of the demyelination and remyelination processes of neuronal axons, the culture of dissociated cerebellar cell culture of the 7-day-old FVB/N lineage mice was used. To detect the myelin sheaths, a histochemical staining with a Sudan Black B was used. To identify oligodendrocytes, immunocytochemical staining of 28-30-old-day cerebellar cells cultures for oligodendrocytes marker Olig2 was performed.Results. The direct effect of the demyelinating factor of cuprizone and remyelination agents (rhLIF and melatonin) on oligodendrocytes in vitro was confirmed. The remyelinating effect of LIF and melatonin on the restoration of myelination processes in dissociated cerebellar cell culture using histochemical and immunocytochemical staining has been revealed.Conclusions. Cuprizone-induced demyelination in vitro is associated with the death of Olig2+ oligodendrocytes and loss of myelin formation. rhLIF and melatonin are prevented the loss of oligodendrocytes and, consequently, reduced the destruction of myelin membranes.