Proc Natl Acad Sci U S A. 2016. pii: 201523869. [Epub ahead of print]
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.
In this weeks PNas, we have a EAE cure of the week. In EAE we see many, many studies that indicate that Th17 = bad and Treg production = good. This study indicates that Protein kinase CK2 (‘casein kinase II’) is a pivotal molecule in controlling these pathways to block Th17 function and to promote Treg function. If you want to read more about the molecule (click here)
In MS the dury is out…as blocking IL-17 to block Th17 function is not that great so far and reduction of T reg numbers with daclizumab is associated with benefit.
PKCK2 has been classified as a messenger-independent protein serine/threonine kinase (an enzyme inside a cell) that is typically found in tetrameric (four unit) complexes consisting of two catalytic (alpha and/or alpha’) subunits and two regulatory beta subunits. Accumulated biochemical and genetic evidence indicates that CK2 has a vast array of candidate physiological targets and participates in a complex series of cellular functions, including the maintenance of cell viability.
So this says that many cell processes may use this molecule and therefore persistent blockage may be associated with lots of side effects, such as defects in developing sperm which are found in some knockout mice.
The problem with targeting such molecules is that not only does the drug have to reach the cell but it also has to get inside it to do its function. The specificity of cell function is often at the cell surface and molecules inside the cell are harnessed to do many different functions so blockage to target on function can target other functions.Therefore scientifically interesting but as a treatment I won’t be holding my breath. However this is just an opinion.