title: Sustained stabilization of Interleukin-8 mRNA in human macrophages.
abstract: The mRNAs of most inflammatory mediators are short-lived due to AU-rich elements (AREs) in their 3'-untranslated regions. AREs ensure a low basal level of expression during homeostasis and a transient nature of expression during the inflammatory response. Here, we report that the mRNA of the pro-inflammatory chemokine IL-8, which contains an archetypal ARE, is unexpectedly constitutively abundant and highly stable in primary human monocytes and macrophages. Using the pre-monocyte-like THP-1 cell line that can differentiate into macrophage-like cells, we show that a low level of unstable IL-8 mRNA in undifferentiated cells (half-life<30 min) becomes constitutively elevated and the mRNA is dramatically stabilized in differentiated THP-1 cells with a half-life of more than 15 h similar to primary monocytes and macrophages. In contrast, the level and stability of TNF-α mRNA also containing an ARE is only slightly affected by differentiation; it remains low and unstable in primary macrophages and differentiated THP-1 cells with an estimated half-life of less than 20 min. This differentiation-dependent stabilization of IL-8 mRNA is p38 MAPK-independent and is probably coupled with reduced protein translation. Reporter assays in THP-1 cells suggest that the ARE alone is not sufficient for the constitutive stabilization in macrophage-like cells and imply an effect of the natural biogenesis of the transcript on the stabilization of the mature form. We present a novel, cell type-dependent sustained stabilization of an ARE-containing mRNA with similarities to situations found in disease.
authors: Molecular Biomedicine Program; King Faisal Specialist Hospital and Research Center; Riyadh, Saudi Arabia.
authors: Linah
authors: L
authors: Mahmoud
authors: Molecular Biomedicine Program; King Faisal Specialist Hospital and Research Center; Riyadh, Saudi Arabia; Department of Biochemistry; King Saud University; Riyadh, Saudi Arabia.
authors: Fatma
authors: F
authors: Al-Enezi
authors: Molecular Biomedicine Program; King Faisal Specialist Hospital and Research Center; Riyadh, Saudi Arabia.
authors: Maher
authors: M
authors: Al-Saif
authors: Department of Biochemistry; King Saud University; Riyadh, Saudi Arabia.
authors: Arjumand
authors: A
authors: Warsy
authors: Molecular Biomedicine Program; King Faisal Specialist Hospital and Research Center; Riyadh, Saudi Arabia.
authors: Khalid S A
authors: KS
authors: Khabar
authors: Molecular Biomedicine Program; King Faisal Specialist Hospital and Research Center; Riyadh, Saudi Arabia.
authors: Edward G
authors: EG
authors: Hitti
mesh_terms: D063307:AU Rich Elements / Q000502:physiology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D003609:Dactinomycin / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; D019384:Nucleic Acid Synthesis Inhibitors; D010703:Phorbol Esters; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin
keywords: AU-rich elements; CXCL-8; IL-8; mRNA stability; macrophages; monocytes