Distinct functions of the MAPKAP kinases MK2 and MK3 in the regulation of the inflammatory response in macrophages

The liver is highly exposed to foreign, in particular gut-derived material and as an important immune organ it harbours the bodies’ largest pool of macrophages, which are predominantly located in the periportal area to screen infiltrating pathogens. In macrophages the bacterial component lipopolysaccharide (LPS) induces the expression of pro- and anti-inflammatory target genes. A tightly controled induction of these target genes is important to prevent severe hepatocyte damage due to an overwhelming inflammatory response. p38^MAPK-mediated activation of MK2 and MK3 is essential for the production and the control of several LPS-induced inflammatory factors such as the cytokines TNFα, IL–1β, IL–6, IL–10 and IFNγ. In addition, own experiments reveal that the expression of IFNβ and OSM is regulated by MK2 and MK3. This suggests that in macrophages the p38^MAPK/MK2/MK3 pathway holds a key position in propagating the inflammatory response. Previous reports so far indicate that in this context MK2 is of key importance for the regulation of LPS-induced cytokine expression whereas MK3, as a homolog of MK2, acts in a cooperative manner and supports MK2 function, but it does not play a self-contained role. In our present study evidence is provided that MK3 and MK2 also have opposing roles with MK3, in the absence of MK2, acting as an inhibitor of IFNβ expression as it blocks NFκB- and IRF3-dependent signaling induced by LPS. MK2 is required for the control of IFNβ expression as it neutralizes these inhibitory effects of MK3. Preliminary data further suggest that MK2 likewise controls IL–27 and DUSP1 gene expression by inhibiting negative regulatory effects of MK3. This is in clear contrast to the regulation of other genes such as IL–6, IL–10, OSM and TNFα, which all are cooperatively regulated by MK2 and MK3. We propose that in macrophages the interplay between these two kinases is of key importance for the expression and composition of inflammatory mediators induced by LPS.

cytokines - inflammation - interferon - macrophages - signal transduction