title: IL-23 mediates inflammatory responses to mucoid Pseudomonas aeruginosa lung infection in mice.
abstract: Patients with cystic fibrosis (CF) develop chronic Pseudomonas aeruginosa lung infection with mucoid strains of P. aeruginosa; these infections cause significant morbidity. The immunological response in these infections is characterized by an influx of neutrophils to the lung and subsequent lung damage over time; however, the underlying mediators to this response are not well understood. We recently reported that IL-23 and IL-17 were elevated in the sputum of patients with CF who were actively infected with P. aeruginosa; however, the importance of IL-23 and IL-17 in mediating this inflammation was unclear. To understand the role that IL-23 plays in initiating airway inflammation in response to P. aeruginosa, IL-23p19(-/-) (IL-23 deficient) and wild-type (WT) mice were challenged with agarose beads containing a clinical, mucoid isolate of P. aeruginosa. Levels of proinflammatory cytokines, chemokines, bacterial dissemination, and inflammatory infiltrates were measured. IL-23-deficient mice had significantly lower induction of IL-17, keratinocyte-derived chemokine (KC), and IL-6, decreased bronchoalveolar lavage (BAL) neutrophils, metalloproteinase-9 (MMP-9), and reduced airway inflammation than WT mice. Despite the reduced level of inflammation in IL-23p19(-/-) mice, there were no differences in the induction of TNF and interferon-gamma or in bacterial dissemination between the two groups. This study demonstrates that IL-23 plays a critical role in generating airway inflammation observed in mucoid P. aeruginosa infection and suggests that IL-23 could be a potential target for immunotherapy to treat airway inflammation in CF.
authors.affiliation: Division of Pediatric Pulmonology, Children's Hospital of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Dubin
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D018925:Chemokines / Q000378:metabolism; D015169:Colony Count, Microbial; D005786:Gene Expression Regulation; D006025:Glycosaminoglycans / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D020381:Interleukin-17 / Q000378:metabolism; D053759:Interleukin-23 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000201:enzymology / Q000382:microbiology* / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008863:Microspheres; D011552:Pseudomonas Infections / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012685:Sepharose
chemical_list: D018925:Chemokines; D006025:Glycosaminoglycans; D020381:Interleukin-17; D053759:Interleukin-23; D012333:RNA, Messenger; C046129:mucoid exopolysaccharide (P aeruginosa); D012685:Sepharose; D020780:Matrix Metalloproteinase 9