Crucial role of the MAPKAP kinases 2 and 3 for pathogen-induced inflammation and their relevance for the immune response of the liver

Excerpt

The liver plays an important role in innate and adaptive immunity and in particular in induction of tolerance. The liver is frequently exposed to pathogens like gut-derived food antigens, environmental toxins and bacterial or viral products reaching the liver via the blood flow. It is central for production of acute phase proteins, among others including protease inhibitors, soluble pattern-recognition receptors and components of the complement system, which are important constituents of innate immunity. The liver harbors the largest pool of sessile tissue macrophages within the body, mainly localized within the periportal area of the sinusoids at a strategically important position. These resident tissue macrophages play a key role for the elimination of opsonized immune complexes by phagocytosis and are important sources of inflammatory cytokines, which induce acute phase protein production in hepatocytes and further trigger innate immunity and subsequent formation of adaptive immunity. Within macrophages the MAPKAP kinases (MK)2 and 3, which represent downstream targets of the MAP kinase family member p38^MAPK, are known to own key functions in the coordination of the inflammatory response. Thereby, their role for the regulation of the expression of inflammatory as well as anti-inflammatory cytokines, such as TNF-α, IL-1β, IL-6, IFN-γ and IL-10 has been mainly investigated in the context of bacterial components and in particular in the context of lipopolysaccharide (LPS). In this context MK2 and MK3 have been suggested to act in a co-operative manner as the expression of these cytokines is abrogated upon deletion of MK2 and is further diminished by the additional deletion of MK3. However, while investigating the role of MK2 and MK3 for the regulation of LPS-induced IFN-β production our group recently provided evidence that MK2 and MK3 are also able to exert rather distinct than co-operative regulatory effects on gene expression [1]. At the current stage the data suggest that these distinct regulatory effects of MK2 and MK3 become apparent, if regulation of respective target gene expression by these two kinases exclusively occurs at the level of transcription and does not involve post-transcriptional regulatory mechanisms such as regulation of transcript stability. Contrariwise, if regulation of gene expression by MK2 and MK3 occurs at the level of transcript stability these two kinases mainly seem to act co-operatively. Thus, MK2 and to a lesser extent MK3 are critical for regulation of TNF-α, IL-6 and IL-10 in response to LPS, where they are involved in control of transcript stability or translation. This is in contrast to the regulation of IFN-β gene expression by MK2 and MK3 where MK2 controls IFN-β gene expression by neutralizing inhibitory effects of MK3, which in the absence of MK2 inhibits transcriptional activation of IFN-β gene expression by impeding IRF-3 protein expression as well as LPS-induced nuclear translocation of NFκB [1]. Of note, unlike for example regulation of LPS-induced IL-10 expression, which essentially requires MK2 for stabilization of the IL-10 transcript, the stability of the IFN-β transcript does not require the presence of MK2. …