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MK2 and MK3 regulate LPS-induced inflammatory response of macrophages [120min]

ABSTRACT: The p38MAPK downstream targets MK 2 and 3 are critical for the regulation of the macrophage response towards bacterial lipopolysaccharid (LPS). The extent these two kinases act cooperatively in regulating LPS-induced inflammatory cytokine expression and their distinct regulatory effects are still unclear. To address this point, whole transcriptome analyses had been performed using bone marrow derived macrophages (BMDM) generated from MK2-/- or MK2/3-/- animals and from wildtype littermates. The BMDM were treated with 100 ng/ml LPS for 120 minutes or with medium as control. Thereafter, total mRNA was isolated and subjected to array analysis using the SurePrint G3 Mouse 8x60K Microarray Kit from Agilent.

ORGANISM(S): Mus musculus

PROVIDER: GSE123041 | GEO | 2019/07/30

REPOSITORIES: GEO

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Project description:Background: Differentiated hepatocytes are long-lived and normally do not undergo cell division, however they have the unique capacity to autonomously decide their replication fate after liver injury. In this context, the key players of liver regeneration immediately after injury have not been adequately studied. Using an in vitro liver culture system, we show that after liver injury, p38 mitogen-activated protein kinase (p38MAPK), mitogen-activated protein kinase-activated protein kinase 2 (MK2) and extracellular-signal regulated kinase (Erk)1/2 were activated within 15 min and continued to be phosphorylated for more than 2 h. Both p38MAPK and Erk1/2 were activated at the edge of the cut as well as on the liver surface where the mesothelial cell sheet expresses several cytokines. Notably, in human liver Erk1/2 was also activated under the mesothelial cell sheet shortly after liver resections. Furthermore, in in vitro liver slice culture immediate early genes (IEGs) were upregulated within 1-2 h and the S phase marker proliferation-cell-nuclear-antigen (PCNA) appeared 24 h after injury. Although Erk1/2 was activated after injury, in MK2 depleted liver a set of IEGs, such as Dusp1, Cox2, or c-Myc and proliferation marker gene Ki67 were not induced. In addition, in immortalized hepatocyte cells, THLE-2, the same subset of genes was upregulated upon stimulation with lipopolysaccharide (LPS), but not in the presence of MK2 inhibitor. The protein level of tristetraprolin (TTP), a substrate for MK2 that plays a role in mRNA degradation, was increased in the presence of MK2 inhibitor. In this context, the depletion of TTP gene rescued Dusp1, Cox2, or c-Myc upregulation in the presence of MK2 inhibitor. These data imply that MK2 pathway is positively involved in Erk1/2 induced IEG response after liver injury. These data also suggest that in vitro liver culture may be a useful tool for measuring the proliferation potential of hepatocytes in individual liver.

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MK2 and MK3 regulate LPS-induced inflammatory response of macrophages [120min]

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