title: A Wnt/β-catenin negative feedback loop represses TLR-triggered inflammatory responses in alveolar epithelial cells.
abstract: Increasing evidence has demonstrated that the epithelial cells in the lung play crucial roles in regulating certain inflammatory responses by modulating Wnt signaling during microbial infection. However, the anti-microbial functions of Wnt signaling in alveolar epithelial cells remain elusive. In this report, we show that Wnt/β-catenin signaling is repressed in A549 alveolar epithelial cells during a Toll-like receptor ligand stimulation with Mycobacterium bovis Bacillus Calmette-Guerin (BCG) or lipopolysaccharide (LPS). In addition to activating TLR signaling, a stimulation of BCG or LPS led to the up-regulation of a Wnt receptor Frizzled-1, cytosolic GSK3β and Axin, and the down-regulation of nuclear β-catenin, lymphoid enhancer factor 1 and transcription factor 4. While an enhancement of β-catenin activity suppressed the TLR signal response, and substantially led to alleviate the TLR ligand-induced pro-inflammatory responses. Importantly, gain and loss of function studies by overexpressing or silencing of TLR signaling adaptor, myeloid differentiation primary response gene 88 (MyD88) further demonstrated an inverse relationship between TLR signaling and canonical Wnt signaling in A549 cells. These data imply that Wnt/β-catenin signaling acts as a negative feedback loop to suppress inflammation in alveolar epithelial cells, and averts cell injury from excessive inflammatory reactions. This study thus reveals a novel immunoregulatory mechanism in alveolar epithelial cells in response to bacterial infection.
authors.affiliation: Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, Ningxia University, Yinchuan, Ningxia 750021, China; College of Life Science, Ningxia University, Yinchuan, Ningxia 750021, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, Ningxia University, Yinchuan, Ningxia 750021, China; College of Life Science, Ningxia University, Yinchuan, Ningxia 750021, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Shi
authors.affiliation: Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, Ningxia University, Yinchuan, Ningxia 750021, China; College of Life Science, Ningxia University, Yinchuan, Ningxia 750021, China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Yang
authors.affiliation: Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, Ningxia University, Yinchuan, Ningxia 750021, China; College of Life Science, Ningxia University, Yinchuan, Ningxia 750021, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, Ningxia University, Yinchuan, Ningxia 750021, China; College of Life Science, Ningxia University, Yinchuan, Ningxia 750021, China.
authors.forename: Long
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, Ningxia University, Yinchuan, Ningxia 750021, China; College of Life Science, Ningxia University, Yinchuan, Ningxia 750021, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, Ningxia University, Yinchuan, Ningxia 750021, China; College of Life Science, Ningxia University, Yinchuan, Ningxia 750021, China.
authors.forename: Xiujing
authors.initials: X
authors.lastname: Hao
authors.affiliation: Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, Ningxia University, Yinchuan, Ningxia 750021, China; College of Life Science, Ningxia University, Yinchuan, Ningxia 750021, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Ma
authors.affiliation: Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, Ningxia University, Yinchuan, Ningxia 750021, China; College of Life Science, Ningxia University, Yinchuan, Ningxia 750021, China.
authors.forename: Yujiong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, Ningxia University, Yinchuan, Ningxia 750021, China; College of Life Science, Ningxia University, Yinchuan, Ningxia 750021, China. Electronic address: lxm1966@nxu.edu.cn.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Liu
mesh_terms: D060466:Axin Protein / Q000096:biosynthesis; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000096:biosynthesis; D002460:Cell Line; D015536:Down-Regulation; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism; D051157:Frizzled Receptors / Q000096:biosynthesis; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000276:immunology; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000096:biosynthesis; D009163:Mycobacterium bovis / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000276:immunology* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D020545:Respiratory Mucosa / Q000276:immunology; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000096:biosynthesis; D015854:Up-Regulation; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000276:immunology; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D060466:Axin Protein; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C489740:FZD1 protein, human; D051157:Frizzled Receptors; C497573:LEF1 protein, human; D008070:Lipopolysaccharides; D051821:Lymphoid Enhancer-Binding Factor 1; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D034741:RNA, Small Interfering; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: Bacterial infection; Epithelial cells; Inflammatory response; Toll-like receptor signaling; Wnt/β-catenin signaling