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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 Disease¹

Vladislav Dolgachev,^* Bryan C. Petersen,^* Alison L. Budelsky, Aaron A. Berlin,^* and Nicholas W. Lukacs^2*

^*Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and Department of Inflammation, Amgen, Seattle, WA 98119

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported in part by National Institutes of Health Grants HL059178 and AI036302.

² Address correspondence and reprint requests to Dr. Nicholas W. Lukacs, Department of Pathology, University of Michigan Medical School, 4059 BSRB, 109 Zina Pitcher, Ann Arbor, MI 48109. E-mail address: nlukacs{at}umich.edu

³ Abbreviations used in this paper: SCF, stem cell factor; CRA, cockroach allergen; AHR, airway hyperresponsiveness.

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The JI 2009 183: 5435-5436. [Full Text]