title: Interleukin-23 (IL-23)-IL-17 cytokine axis in murine Pneumocystis carinii infection.
abstract: Host defense mechanisms against Pneumocystis carinii are not fully understood. Previous work in the murine model has shown that host defense against infection is critically dependent upon host CD4(+) T cells. The recently described Th17 immune response is predominantly a function of effector CD4(+) T cells stimulated by interleukin-23 (IL-23), but whether these cells are required for defense against P. carinii infection is unknown. We tested the hypothesis that P. carinii stimulates the early release of IL-23, leading to increases in IL-17 production and lung effector CD4(+) T-cell population that mediate clearance of infection. In vitro, stimulation of alveolar macrophages with P. carinii induced IL-23, and IL-23p19 mRNA was expressed in lungs of mice infected with this pathogen. To address the role of IL-23 in resistance to P. carinii, IL-23p19-/- and wild-type control C57BL/6 mice were infected and their fungal burdens and cytokine/chemokine responses were compared. IL-23p19-/- mice displayed transient but impaired clearance of infection, which was most apparent 2 weeks after inoculation. In confirmatory studies, the administration of either anti-IL-23p19 or anti-IL-17 neutralizing antibody to wild-type mice infected with P. carinii also caused increases in fungal burdens. IL-17 and the lymphocyte chemokines IP-10, MIG, MIP-1alpha, MIP-1beta, and RANTES were decreased in the lungs of infected IL-23p19-/- mice in comparison to their levels in the lungs of wild-type mice. In IL-23p19-/- mice infected with P. carinii, there were fewer effector CD4(+) T cells in the lung tissue. Collectively, these studies indicate that the IL-23-IL-17 axis participates in host defense against P. carinii.
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, Louisiana State University, LSU Health Sciences Center, 1901 Perdido Street, New Orleans, LA 70112, USA.
authors.forename: Xiaowen L
authors.initials: XL
authors.lastname: Rudner
authors.forename: Kyle I
authors.initials: KI
authors.lastname: Happel
authors.forename: Erana A
authors.initials: EA
authors.lastname: Young
authors.forename: Judd E
authors.initials: JE
authors.lastname: Shellito
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D006790:Host-Parasite Interactions / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000378:metabolism*; D053759:Interleukin-23 / Q000172:deficiency* / Q000502:physiology; D008168:Lung / Q000276:immunology* / Q000469:parasitology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011010:Pneumocystis / Q000276:immunology*; D011020:Pneumonia, Pneumocystis / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D020381:Interleukin-17; D053759:Interleukin-23