title: Hyaluronic acid or TNF-alpha plus fibronectin triggers granulocyte macrophage-colony-stimulating factor mRNA stabilization in eosinophils yet engages differential intracellular pathways and mRNA binding proteins.
abstract: Eosinophils (Eos) accumulate in airways and lung parenchyma of active asthmatics. GM-CSF is a potent inhibitor of Eos apoptosis both in vitro and in vivo and is produced by activated fibroblasts, mast cells, T lymphocytes as well as Eos. Cytokine release by Eos is preceded by GM-CSF mRNA stabilization induced by TNF-alpha plus fibronectin. Hyaluronic acid (HA) is a major extracellular matrix proteoglycan, which also accumulates in the lung during asthma exacerbations. In this study we have analyzed the effects of HA on Eos survival and GM-CSF expression. We demonstrate that like TNF-alpha plus fibronectin, HA stabilizes GM-CSF mRNA, increases GM-CSF secretion, and prolongs in vitro Eos survival. GM-CSF mRNA stabilization accounts for most of the observed GM-CSF mRNA accumulation and protein production. Unlike TNF-alpha plus fibronectin, GM-CSF mRNA stabilization induction by HA requires continuous extracellular signal-regulated kinase phosphorylation. Finally, to identify potential protein regulators responsible for GM-CSF mRNA stabilization, immunoprecipitation-RT-PCR studies revealed increased GM-CSF mRNA associated with YB-1, HuR, and heterogeneous nuclear ribonucleoprotein (hnRNP) C after TNF-alpha plus fibronectin but only hnRNP C after HA. Thus, our data suggest that both TNF-alpha plus fibronectin and HA, which are relevant physiological effectors in asthma, contributes to long-term Eos survival in vivo by enhancing GM-CSF production through two different posttranscriptional regulatory pathways involving extracellular signal-regulated kinase phosphorylation and RNA binding proteins YB-1, HuR, and hnRNP C.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin Medical School, Madison, WI 53792, USA.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Esnault
authors.forename: James S
authors.initials: JS
authors.lastname: Malter
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D002470:Cell Survival / Q000502:physiology; D004338:Drug Combinations; D004804:Eosinophils / Q000166:cytology / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D005353:Fibronectins / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000502:physiology; D006820:Hyaluronic Acid / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D020871:RNA Stability / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D000276:Adjuvants, Immunologic; D004338:Drug Combinations; D005353:Fibronectins; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C; D018960:Hyaluronan Receptors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006820:Hyaluronic Acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases