title: Pulmonary IL-17E (IL-25) production and IL-17RB+ myeloid cell-derived Th2 cytokine production are dependent upon stem cell factor-induced responses during chronic allergic pulmonary disease.
abstract: In the present studies local neutralization of allergen-induced stem cell factor (SCF) leads to decreased production of Th2 cytokines, a reduction in inflammation, allergen-specific serum IgE/IgG1, and attenuation of severe asthma-like responses. The local blockade of pulmonary SCF also resulted in a significant reduction of IL-17E (IL-25). Sorted cell populations from the lung indicated that IL-25 was produced from c-kit(+) cells, whereas Th2 cytokine production was primarily from c-kit(-) cell populations. SCF stimulated c-kit(+) eosinophils produced IL-25, whereas bone marrow-derived mast cells did not. Using 4get mice that contain a IL-4-IRES-eGFP that when transcribed coexpress GFP and IL-4, our studies identified cells that comprised a CD11b(+), GR1(+), Ly6C(+/-), c-kit(-), CD4(-), CD11c(-), MHC class II(low) cell population as a source of IL-4 in the lung after chronic allergen challenge. In the bone marrow a similar cell was identified with approximately a third of the IL-4(+) cells also expressing c-kit(+). The pulmonary and bone marrow IL-4(+) cell populations were significantly reduced upon local pulmonary anti-SCF treatment. Subsequently, when IL-25R was examined during the chronic allergen responses the expression was found on the IL-4(+) myeloid cell population that expressed CD11b(+)GR1(+). Interestingly, the IL-25R(+) cells in the bone marrow were also all CD11b(+)GR1(+), similar to the lung cells, but they were also all c-kit(+), potentially suggesting a maturation of the bone marrow cell once it enters the lung and/or is stimulated by SCF. Overall, these studies suggest a complex relationship between SCF, bone marrow-derived IL-25-responsive myeloid cells, Th2 cytokines, and chronic allergic disease.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Vladislav
authors.initials: V
authors.lastname: Dolgachev
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Petersen
authors.forename: Alison L
authors.initials: AL
authors.lastname: Budelsky
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Berlin
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Lukacs
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D039481:CD11b Antigen / Q000096:biosynthesis; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002908:Chronic Disease; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D020381:Interleukin-17 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis*; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019707:Receptors, Chemokine / Q000096:biosynthesis; D053722:Receptors, Interleukin-17 / Q000096:biosynthesis*; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019089:Stem Cell Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D039481:CD11b Antigen; D016207:Cytokines; C503133:Gr-1 protein, mouse; C486701:IL25 protein, human; C485810:Il17rb protein, mouse; D018836:Inflammation Mediators; D020381:Interleukin-17; D007378:Interleukins; C442281:Mydgf protein, mouse; D019707:Receptors, Chemokine; D053722:Receptors, Interleukin-17; D019089:Stem Cell Factor; D015847:Interleukin-4