title: MK2 posttranscriptionally regulates TNF-α-induced expression of ICAM-1 and IL-8 via tristetraprolin in human pulmonary microvascular endothelial cells.
abstract: Tristetraprolin (TTP), a substrate of p38 mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2), is an RNA-binding protein that binds to AU-rich elements (AREs) in the 3'-untranslated region (3'-UTR) of its target mRNAs and accelerates mRNA degradation. A previous study by our group showed that MK2 regulates tumor necrosis factor-α (TNF-α)-induced expression of intercellular adhesion molecule-1 (ICAM-1) and interleukin-8 (IL-8) in human lung microvascular endothelial cells; however, the downstream protein of MK2 remains unknown. Interestingly, both ICAM-1 and IL-8 have AREs in the 3'-UTR of their mRNAs. In the present study, we performed experiments to determine whether MK2 regulates TNF-α-induced expression of ICAM-1 and IL-8 via TTP in human pulmonary microvascular endothelial cells (HPMECs). The study revealed that MK2 silencing significantly reduced the half-lives of ICAM-1 and IL-8 mRNAs in TNF-α-stimulated HPMECs. TTP phosphorylation levels were decreased in MK2-silenced cells. TTP silencing led to mRNA stabilization of ICAM-1 and IL-8 and upregulation of protein production following TNF-α stimulation. These results, together with our previous study and others, suggest that MK2, in HPMECs, regulates TNF-α-induced expression of ICAM-1 and IL-8 via TTP at the mRNA decay level.
authors.affiliation: Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing University School of Medicine, China.
authors.forename: Jia-Xin
authors.initials: JX
authors.lastname: Shi
authors.forename: Xin
authors.initials: X
authors.lastname: Su
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.forename: Wei-Yun
authors.initials: WY
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
mesh_terms: D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D016209:Interleukin-8 / Q000096:biosynthesis*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008168:Lung / Q000098:blood supply / Q000378:metabolism; D055806:Microvessels / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051816:Tristetraprolin / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D018799:Intercellular Adhesion Molecule-1; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; D000099190:MAP-Kinase-Activated Kinase 2