title: Type I Interferons Function as Autocrine and Paracrine Factors to Induce Autotaxin in Response to TLR Activation.
abstract: Lysophosphatidic acid (LPA) is an important phospholipid mediator in inflammation and immunity. However, the mechanism of LPA regulation during inflammatory response is largely unknown. Autotaxin (ATX) is the key enzyme to produce extracellular LPA from lysophosphatidylcholine (LPC). In this study, we found that ATX was induced in monocytic THP-1 cells by TLR4 ligand lipopolysaccharide (LPS), TLR9 ligand CpG oligonucleotide, and TLR3 ligand poly(I:C), respectively. The ATX induction by TLR ligand was abolished by the neutralizing antibody against IFN-β or the knockdown of IFNAR1, indicating that type I IFN autocrine loop is responsible for the ATX induction upon TLR activation. Both IFN-β and IFN-α were able to induce ATX expression via the JAK-STAT and PI3K-AKT pathways but with different time-dependent manners. The ATX induction by IFN-β was dramatically enhanced by IFN-γ, which had no significant effect on ATX expression alone, suggesting a synergy effect between type I and type II IFNs in ATX induction. Extracellular LPA levels were significantly increased when THP-1 cells were treated with IFN-α/β or TLR ligands. In addition, the type I IFN-mediated ATX induction was identified in human monocyte-derived dendritic cells (moDCs) stimulated with LPS or poly(I:C), and IFN-α/β could induce ATX expression in human peripheral blood mononuclear cells (PBMCs) and monocytes isolated form blood samples. These results suggest that, in response to TLR activation, ATX is induced through a type I INF autocrine-paracrine loop to enhance LPA generation.
authors: Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China.
authors: Jianwen
authors: J
authors: Song
authors: Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry Chinese Academy of Sciences, Beijing, China.
authors: Ming
authors: M
authors: Guan
authors: Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry Chinese Academy of Sciences, Beijing, China.
authors: Zhenwen
authors: Z
authors: Zhao
authors: Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China.
authors: Junjie
authors: J
authors: Zhang
mesh_terms: D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000235:genetics; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008246:Lysophospholipids / Q000096:biosynthesis / Q000235:genetics; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D019899:Paracrine Communication / Q000187:drug effects / Q000502:physiology*; D010727:Phosphoric Diester Hydrolases / Q000096:biosynthesis* / Q000235:genetics; D011070:Poly I-C / Q000494:pharmacology; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000099189:Lysophospholipase D
chemical_list: D016898:Interferon-alpha; D016899:Interferon-beta; D008070:Lipopolysaccharides; D008246:Lysophospholipids; D009838:Oligodeoxyribonucleotides; D010727:Phosphoric Diester Hydrolases; D011070:Poly I-C; D053633:Receptor, Interferon alpha-beta; D051193:Toll-Like Receptors; D000099189:Lysophospholipase D; C408982:CPG-oligonucleotide; C507964:IFNAR1 protein, human; C032881:lysophosphatidic acid