Format

Send to

Choose Destination
Sci Rep. 2019 Jul 30;9(1):11021. doi: 10.1038/s41598-019-46791-8.

Cooperative and distinct functions of MK2 and MK3 in the regulation of the macrophage transcriptional response to lipopolysaccharide.

Author information

1
Clinic for Gastroenterology, Hepatology and Infectiology, University Hospital, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
2
Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany.
3
Biological and Medical Research Center (BMFZ), Genomics & Transcriptomics Laboratory, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
4
Institute of Cell Biochemistry, Hannover Medical School, Hannover, Germany.
5
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
6
Clinic for Gastroenterology, Hepatology and Infectiology, University Hospital, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany. Johannes.Bode@med.uni-duesseldorf.de.

Abstract

The p38MAPK downstream targets MAPKAP kinases (MK) 2 and 3 are critical for the regulation of the macrophage response to LPS. The extents to which these two kinases act cooperatively and distinctly in regulating LPS-induced inflammatory cytokine expression are still unclear. To address this uncertainty, whole transcriptome analyses were performed using bone marrow-derived macrophages (BMDM) generated from MK2-/- or MK2/3-/- animals and their wild-type littermates. The results suggest that in BMDM, MK2 and MK3 not only cooperatively regulate the transcript expression of signaling intermediates, including IL-10, IL-19, CXCL2 and the IL-4 receptor (IL-4R)α subunit, they also exert distinct regulatory effects on the expression of specific transcripts. Based on the differential regulation of gene expression by MK2 and MK3, at least six regulatory patterns were identified. Importantly, we confirmed our previous finding, which showed that in the absence of MK2, MK3 negatively regulates IFN-β. Moreover, this genome-wide analysis identified the regulation of Cr1A, NOD1 and Serpina3f as similar to that of IFN-β. In the absence of MK2, MK3 also delayed the nuclear translocation of NFκB by delaying the ubiquitination and subsequent degradation of IκBβ, reflecting the substantial plasticity of the response of BMDM to LPS.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center