Role of IL-17A, IL-17F, and the IL-17 receptor in regulating growth-related oncogene-alpha and granulocyte colony-stimulating factor in bronchial epithelium: implications for airway inflammation in cystic fibrosis.
IL-17R signaling is critical for pulmonary neutrophil recruitment and host defense against Gram-negative bacteria through the coordinated release of G-CSF and CXC chemokine elaboration. In this study, we show that IL-17R is localized to basal airway cells in human lung tissue, and functional IL-17R signaling occurs on the basolateral surface of human bronchial epithelial (HBE) cells. IL-17A and IL-17F were potent inducers of growth-related oncogene-alpha and G-CSF in HBE cells, and significant synergism was observed with TNF-alpha largely due to signaling via TNFRI. The activities of both IL-17A and IL-17F were blocked by a specific anti-IL-17R Ab, but only IL-17A was blocked with a soluble IL-17R, suggesting that cell membrane IL-17R is required for signaling by both IL-17A and IL-17F. Because IL-17A and IL-17F both regulate lung neutrophil recruitment, we measured these molecules as well as the proximal regulator IL-23p19 in the sputum of patients with cystic fibrosis (CF) undergoing pulmonary exacerbation. We found significantly elevated levels of these molecules in the sputum of patients with CF who were colonized with Pseudomonas aeruginosa at the time of pulmonary exacerbation, and the levels declined with therapy directed against P. aeruginosa. IL-23 and the downstream cytokines IL-17A and IL-17F are critical molecules for proinflammatory gene expression in HBE cells and are likely involved in the proinflammatory cytokine network involved with CF pathogenesis.
McAllister
Florencia
F
Lung Immunology and Host Defense Laboratory, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Henry
Adam
A
Kreindler
James L
JL
Dubin
Patricia J
PJ
Ulrich
Lauren
L
Steele
Chad
C
Finder
Jonathan D
JD
Pilewski
Joseph M
JM
Carreno
Beatriz M
BM
Goldman
Samuel J
SJ
Pirhonen
Jaana
J
Kolls
Jay K
JK
D001980:Bronchi / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002462:Cell Membrane / Q000276:immunology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000276:immunology* / Q000378:metabolism*; D004848:Epithelium / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism* / Q000494:pharmacology; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000378:metabolism; D007700:Kinetics; D011552:Pseudomonas Infections / Q000276:immunology / Q000378:metabolism; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053722:Receptors, Interleukin-17; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C111835:CCL2 protein, human; C475829:CXCL1 protein, human; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C440021:IL17F protein, human; C109985:IL17RA protein, human; C508840:IL23A protein, human; D036341:Intercellular Signaling Peptides and Proteins; D020381:Interleukin-17; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor