Differential regulation of anti-inflammatory genes by p38 MAP kinase kinase 6
Several p38α inhibitors have been developed and evaluated in RA. However, despite pre-clinical data showing promise, the compounds have been shown to have little therapeutic efficacy. Previous studies have suggested this may be a result of inhibitors blocking the role of p38 in limiting inflammation.
Previous studies by the same authors have shown that the targeting of MKK3 or MKK 6, which are the upstream activators of p38, may be superior to p38 blockade as the anti-inflammatory effects will be preserved.
This study explored the potential mechanisms by which p38 inhibition and MKK3- or MKK6-deficiency differentially regulates IL-10 production in bone marrow-derived macrophages.
The blockade of p38 inhibits the expression of IL-10 and p38-dependent anti-inflammatory genes such as DUSP1, TTP and IL-1RA. MKK6-deficiency, in contrast, allowed partial or full induction of IL-10 and TTP which are negative regulators of the inflammatory cascade.
These data suggest MKK6 might be a potential therapeutic target that avoids some of the limitations of a conventional p38 inhibitor.