title: The TNF Family Molecules LIGHT and Lymphotoxin αβ Induce a Distinct Steroid-Resistant Inflammatory Phenotype in Human Lung Epithelial Cells.
abstract: Lung epithelial cells are considered important sources of inflammatory molecules and extracellular matrix proteins that contribute to diseases such as asthma. Understanding the factors that stimulate epithelial cells may lead to new insights into controlling lung inflammation. This study sought to investigate the responsiveness of human lung epithelial cells to the TNF family molecules LIGHT and lymphotoxin αβ (LTαβ). Bronchial and alveolar epithelial cell lines, and primary human bronchial epithelial cells, were stimulated with LIGHT and LTαβ, and expression of inflammatory cytokines and chemokines and markers of epithelial-mesenchymal transition and fibrosis/remodeling was measured. LTβ receptor, the receptor shared by LIGHT and LTαβ, was constitutively expressed on all epithelial cells. Correspondingly, LIGHT and LTαβ strongly induced a limited but highly distinct set of inflammatory genes in all epithelial cells tested, namely the adhesion molecules ICAM-1 and VCAM-1; the chemokines CCL5, CCL20, CXCL1, CXCL3, CXCL5, and CXCL11; the cytokines IL-6, activin A and GM-CSF; and metalloproteinases matrix metalloproteinase-9 and a disintegrin and metalloproteinase domain-8. Importantly, induction of the majority of these inflammatory molecules was insensitive to the suppressive effects of the corticosteroid budesonide. LIGHT and LTαβ also moderately downregulated E-cadherin, a protein associated with maintaining epithelial integrity, but did not significantly drive production of extracellular matrix proteins or α-smooth muscle actin. Thus, LIGHT and LTαβ induce a distinct steroid-resistant inflammatory signature in airway epithelial cells via constitutively expressed LTβ receptor. These findings support our prior murine studies that suggested the receptors for LIGHT and LTαβ contribute to development of lung inflammation characteristic of asthma and idiopathic pulmonary fibrosis.
authors.affiliation: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Ricardo
authors.identifier: http://orcid.org/0000-0001-9785-5272
authors.initials: R
authors.lastname: da Silva Antunes
authors.affiliation: Janssen Research and Development, Immunology Discovery Research, Spring House, PA 19002; and.
authors.forename: Lisa
authors.initials: L
authors.lastname: Madge
authors.affiliation: Janssen Research and Development, San Diego, CA 92121.
authors.forename: Pejman
authors.initials: P
authors.lastname: Soroosh
authors.affiliation: Janssen Research and Development, Immunology Discovery Research, Spring House, PA 19002; and.
authors.forename: Joel
authors.initials: J
authors.lastname: Tocker
authors.affiliation: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; mick@lji.org.
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
mesh_terms: D001980:Bronchi / Q000166:cytology; D019819:Budesonide / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D018836:Inflammation Mediators / Q000378:metabolism*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D053361:Lymphotoxin alpha1, beta2 Heterotrimer / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000235:genetics / Q000378:metabolism; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000494:pharmacology*
chemical_list: D015815:Cell Adhesion Molecules; D018925:Chemokines; D016207:Cytokines; D005938:Glucocorticoids; D018836:Inflammation Mediators; D053361:Lymphotoxin alpha1, beta2 Heterotrimer; D018102:Receptors, Leukotriene B4; D053240:Receptors, Tumor Necrosis Factor, Member 14; C506028:TNFRSF14 protein, human; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D019819:Budesonide