The inflammatory response and acute phase reaction in the liver upon LPS-treatment or partial hepatectomy is controlled by the MAPKAP kinases 2 and 3

The liver plays a pivotal role in innate and adaptive immunity and is critically involved in the acute phase response. Moreover, it has a high capacity of regeneration upon damage. The liver's resident tissue macrophages, which are an essential source of inflammatory cytokines, regulate the production of acute phase proteins by hepatocytes. Within macrophages the MAPKAP kinases (MK)2 and 3, which are downstream targets of the MAP kinase family member p38^MAPK, coordinate the inflammatory outcome as they regulate cytokine and chemokine synthesis in response to pathogens or pathogen associated molecular patterns (PAMP) such as the bacterial component lipopolysaccharide (LPS). In case of cytokines like TNF-α MK2 and MK3 act cooperatively. It has been shown that serum levels of TNF-α are abrogated upon deletion of MK2 and further diminished by additional deletion of MK3.

However, at least in macrophages we demonstrated that MK2 and MK3 are also able to exert rather distinct than cooperative regulatory effects on gene expression as shown for IFN-β. This indicates that the interplay of MK2 and MK3 comprises variable modes of expression patterns regarding distinct target genes. However, the outcome in the serum upon LPS injection in vivo and the relevance for the acute phase response remains to be elucidated and was subject of this study. Furthermore, we were interested wether MK2 and MK3 play also a role for the orchestration of cytokine and chemokine expression in the context of liver regeneration after surgical intervention like partial hepatectomy. We analysed serum as well as liver tissue of LPS-treated or liver resected mice with wildtype, MK2^-/-, MK3^-/- or MK2/3^-/- genotype by milliplex and fluidigm analyses regarding expressed signaling molecules like cytokines, chemokines and acute phase proteins. Our data suggest, that upon deletion of MK2 or MK3 or of both kinases and after LPS treatment there are large groups of genes which are deregulated, whereas after liver surgery there is only a small number of target genes which show an impaired expression pattern, among others IL-6 representing an important co-factor for hepatocyte proliferation. Understanding the mechanisms that control the expression of cytokines, chemokines and acute phase proteins is important for the development of therapies that maintain resolution of inflammation as well as regular liver regeneration.

Therefore, we conclude that in the context of inflammation and acute phase response the interplay of MK2 and MK3 controls a large subset of LPS-induced genes in vivo, whereas after partial hepatectomy it exerts rather a restrictive but specific function.