casein-kinase-ii and Multiple-Sclerosis

Although it has historically been studied in the context of cancer, recent literature has highlighted the importance of the highly conserved serine/threonine kinase casein kinase II (CK2) in inflammatory disorders. Most strikingly, CK2 is a major regulator of the Th17-Treg axis relevant to many T cell-driven autoimmune disorders including multiple sclerosis (MS).

Topics: Animals; Autoimmune Diseases; Casein Kinase II; Clinical Trials as Topic; Emodin; Humans; Immunity; Immunomodulation; Inflammation; Mice; Molecular Targeted Therapy; Multiple Sclerosis; Naphthyridines; Neoplasms; Phenazines; Signal Transduction; T-Lymphocytes, Regulatory; Th17 Cells

Oxidative stress and inflammation play key roles in the pathogenesis of Multiple sclerosis (MS). Different drugs have been used in the clinical practice, however, there is not a completely effective treatment. Due to its potential therapeutic action, medical ozone represents a promising approach for neurodegenerative disorders. The aim of the present study was to address the role of ozone therapy on the cellular redox state in MS patients. Ozone (20μg/ml) was administered three times per week during a month by rectal insufflation. The effect of ozone therapy on biomarkers of oxidative stress and inflammation was addressed by spectrophotometric and immunoenzymatic assays. Furthermore, we investigated the action of ozone on CK2 expression and Nrf2 phosphorylation by western blotting analysis. Medical ozone significantly improved (P < 0.05) the activity of antioxidant enzymes and increased the levels of cellular reduced glutathione. In accordance, a significant reduction (P < 0.05) of oxidative damage on lipids and proteins was observed in ozone-treated patients. As well, the levels of pro-inflammatory cytokines TNFα and IL-1β were lower after ozone treatment. Ozone therapy incremented the CK2 expression together with Nrf2 phosphorylation in mononuclear cells of MS patients. These findings suggest that ozone´s antioxidant and anti-inflammatory effects might be partially associated with an induction of Nrf2 phosphorylation and activation. These results provide new insights on the molecular events modulated by ozone, and pointed out ozone therapy as a potential therapeutic alternative for MS patients.

Topics: Adult; Casein Kinase II; Cytokines; Female; Gene Expression Regulation, Enzymologic; Humans; Inflammation; Male; Middle Aged; Multiple Sclerosis; NF-E2-Related Factor 2; Oxidative Stress; Ozone; Phosphorylation; Signal Transduction; Young Adult

T helper 17 (TH17) cells represent a discrete TH cell subset instrumental in the immune response to extracellular bacteria and fungi. However, TH17 cells are considered to be detrimentally involved in autoimmune diseases like multiple sclerosis (MS). In contrast to TH17 cells, regulatory T (Treg) cells were shown to be pivotal in the maintenance of peripheral tolerance. Thus, the balance between Treg cells and TH17 cells determines the severity of a TH17 cell-driven disease and therefore is a promising target for treating autoimmune diseases. However, the molecular mechanisms controlling this balance are still unclear. Here, we report that pharmacological inhibition as well as genetic ablation of the protein kinase CK2 (CK2) ameliorates experimental autoimmune encephalomyelitis (EAE) severity and relapse incidence. Furthermore, CK2 inhibition or genetic ablation prevents TH17 cell development and promotes the generation of Treg cells. Molecularly, inhibition of CK2 leads to reduced STAT3 phosphorylation and strongly attenuated expression of the IL-23 receptor, IL-17, and GM-CSF. Thus, these results identify CK2 as a nodal point in TH17 cell development and suggest this kinase as a potential therapeutic target to treat TH17 cell-driven autoimmune responses.

Topics: Animals; Casein Kinase II; Encephalomyelitis, Autoimmune, Experimental; Forkhead Transcription Factors; Gene Expression Regulation; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-17; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Phosphorylation; Receptors, Interleukin; Severity of Illness Index; Signal Transduction; STAT3 Transcription Factor; T-Lymphocytes, Regulatory; Th17 Cells