The MAPKAP kinase 2 controls IL-10 expression and protects from liver injury upon cytomegalovirus infection

The anti-inflammatory cytokine IL-10 inhibits the activity of Th1 cells, NK cells and macrophages, which are required for optimal pathogen clearance, but also contribute to tissue damage during infection. Cytomegalovirus (CMV) infection induces the expression of IL-10 to limit immune cell activation and to suppress IFNγ induced MHC class II surface expression, thereby escaping anti-viral mechanisms and diminishing the pro-inflammatory response. This appears to be of particular importance for the prevention of CMV-induced liver injury as suggested from studies on IL-10-deficient mice, which upon infection with MCMV develop an exaggerated pro-inflammatory cytokine response and enhanced liver injury, characterized by increased induction of apoptotic cell death and enlarged cellular infiltrates. However, the molecular mechanisms involved in CMV-induced IL-10 expression are unclear.

The present study analyses the role of the MAPKAP kinase (MK)2 for MCMV-infection in vivo and addresses its relevance for virus-induced IL-10 expression in vitro and in vivo. Evidence is provided, that in macrophages MK2 is critical for MCMV-induced IFNβ expression, which is a prerequisite for sustained IL-10 production in response to MCMV infection as suggested from studies using antagonizing antibodies specific for the type interferon alpha receptor (IFNAR)1. Apart from this, MK2 is further essential for stabilization of the IL-10 transcript. Thereby MK2 regulates IL-10 transcript stability most likely by inhibiting destabilizing effects of TTP, which is demonstrated to be induced by MCMV and to destabilize the IL-10 transcript. Interestingly, apart from IL-10, the production of the inflammatory cytokines TNF-α and IL-6 in vivo was also substantially impaired in the absence of MK2, whereas the production of IFNγ remained intact. This undisturbed IFNγ production and the relative lack of IL-10 may be responsible for the fact that the pathologies observed in MCMV infected MK2 deficient mice closely resembles to that developed by IL-10 deficient mice upon infection with MCMV. Like in IL-10 deficient mice MK2 deficient mice predominantly develop liver pathology characterized by enhanced induction of apoptotic cell death and formation of inflammatory infiltrates, which is almost absent in respective MCMV-infected controls, whereas they have no defect in viral clearance.