MAPKAPK 2 impedes hepcidin mRNA expression and maintains iron availability in response to bacterial endotoxins

Background & aims The liver contributes to innate immunity towards pathogens by the synthesis of acute phase proteins (APP). These proteins minimize tissue damage and promote repair processes. They isolate and neutralize invading pathogens and prevent further pathogen entry. Some of them including the antimicrobial peptide hepcidin also maintain iron homeostasis. The expression of APP by hepatocytes is regulated by inflammatory cytokines and chemokines, which are released by non-parenchymal cells like macrophages and tightly controlled by the intracellular MAPKAP kinase (MK)2. So far, it is unknown, if MK2 plays a role for the synthesis of APP in the liver. Aim of this study is to reveal MK2-dependent mechanisms involved in the regulation of APP and in particular hepcidin expression.

Methods MK2^-/- mice and wildtype mice were treated with 1 μg LPS per g body weight. Animals were sacrificed after incubation periods up to 48 hours. Serum and liver were prepared and subjected to transcript or protein analyses. For in vitro experiments murine hepatocytes were isolated and incubated with cytokines or with the supernatants of LPS-treated bone marrow derived macrophages (BMDM) and analyzed for transcript or protein expression.

Results Following LPS injection MK2 deficiency leads to an abrogation of chemokine and cytokine synthesis including IL-6, whereas transcript expression of only one APP, namely alpha-2-macroglobulin is abolished. Interestingly, serum levels of IL-1β are not diminished and expression of hepcidin mRNA is even more enhanced upon deletion of MK2 when compared to wildtype. This enhancement is independent from transcriptional regulation via STAT3, which is an essential mediator of APP expression and unaffected by MK2 in this content. Moreover, we observed defects in iron availability in MK2^-/- animals.

Conclusion Regarding the dramatic collapsing effect of ubiquitous MK2 deficiency on LPS-induced synthesis of cytokines and chemokines, it is an interesting observation that in the liver MK2 is almost neglectable for the expression of most of the APP. However, MK2 impedes expression of hepcidin mRNA via a post-transcriptional mechanism that is controlled by the cross-talk of IL-6 and IL-1β, but independent from STAT3. We propose that this is important for the regulation of iron homeostasis in vivo. This observation should be of particular interest in view of the increasing number of potential indications for MK2 blockade as a therapeutic approach.

Publication History

Article published online:
04 January 2021