title: IL-17A and TNF-α exert synergistic effects on expression of CXCL5 by alveolar type II cells in vivo and in vitro.
abstract: CXCL5, a member of the CXC family of chemokines, contributes to neutrophil recruitment during lung inflammation, but its regulation is poorly understood. Because the T cell-derived cytokine IL-17A enhances host defense by triggering production of chemokines, particularly in combination with TNF-α, we hypothesized that IL-17A would enhance TNF-α-induced expression of CXCL5. Intratracheal coadministration of IL-17A and TNF-α in mice induced production of CXCL1, CXCL2, and CXCL5, which was associated with increased neutrophil influx in the lung at 8 and 24 h. The synergistic effects of TNF-α and IL17A were greatly attenuated in Cxcl5(-/-) mice at 24 h, but not 8 h, after exposure, a time when CXCL5 expression was at its peak in wild-type mice. Bone marrow chimeras produced using Cxcl5(-/-) donors and recipients demonstrated that lung-resident cells were the source of CXCL5. Using differentiated alveolar epithelial type II (ATII) cells derived from human fetal lung, we found that IL-17A enhanced TNF-α-induced CXCL5 transcription and stabilized TNF-α-induced CXCL5 transcripts. Whereas expression of CXCL5 required activation of NF-κB, IL-17A did not increase TNF-α-induced NF-κB activation. Apical costimulation of IL-17A and TNF-α provoked apical secretion of CXCL5 by human ATII cells in a transwell system, whereas basolateral costimulation led to both apical and basolateral secretion of CXCL5. The observation that human ATII cells secrete CXCL5 in a polarized fashion may represent a mechanism to recruit neutrophils in host defense in a fashion that discriminates the site of initial injury.
authors.affiliation: Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, PA 19014, USA.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Junjie
authors.initials: J
authors.lastname: Mei
authors.forename: Linda
authors.initials: L
authors.lastname: Gonzales
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Ning
authors.initials: N
authors.lastname: Dai
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Peggy
authors.initials: P
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Favara
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Malcolm
authors.forename: Susan
authors.initials: S
authors.lastname: Guttentag
authors.forename: G Scott
authors.initials: GS
authors.lastname: Worthen
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000818:Animals; D002464:Cell Migration Inhibition / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000096:biosynthesis; D054426:Chemokine CXCL2 / Q000096:biosynthesis; D054365:Chemokine CXCL5 / Q000096:biosynthesis* / Q000172:deficiency / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D020381:Interleukin-17 / Q000008:administration & dosage / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D018410:Pneumonia, Bacterial / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011650:Pulmonary Alveoli / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000096:biosynthesis; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000096:biosynthesis / Q000502:physiology*
chemical_list: C486263:CXCL5 protein, human; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D054365:Chemokine CXCL5; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; C094739:Cxcl5 protein, mouse; C508717:IL17A protein, human; D018836:Inflammation Mediators; D020381:Interleukin-17; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha