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

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
The Journal of Immunology (Impact Factor: 4.92). 11/2009; 183(9):5705-15. DOI: 10.4049/jimmunol.0901666
Source: PubMed


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.

Download full-text


Available from: Aaron Berlin, Aug 16, 2015
  • Source
    • "Originally identified as homology to IL-17 family members (Fort et al. 2001; Lee et al. 2001), IL-25 was initially found to accumulate in polarized Th2 cells (Fort et al. 2001). Related studies also demonstrated that other cell types from hematopoietic or non-hematopoietic compartments could produce IL-25 under certain circumstances, such as primary bone marrow-derived mast cells upon IgE cross-linking (Ikeda et al. 2003), eosinophils and basophiles upon stem cell factor stimulation (Dolgachev et al. 2009; Wang et al. 2007), lung epithelial cells upon allergic response (Angkasekwinai et al. 2007), and alveolar macrophages after particle inhalation (Kang et al. 2005). The accumulation of IL-25 could also be seen in intestinal epithelial cells and brain capillary endothelial cells (Sonobe et al. 2009; Zaph et al. 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Interleukin (IL)-25 (also known as IL-17E) is a distinct member of the IL-17 cytokine family which induces IL-4, IL-5, and IL-13 expression and promotes pathogenic T helper (Th)-2 cell responses in various organs. IL-25 has been shown to have crucial role between innate and adaptive immunity and also a key component of the protection of gastrointestinal helminthes. In this study, to produce bioactive recombinant human IL-25 (rhIL-25), the cDNA of mature IL-25 was performed codon optimization based on methylotropic yeast Pichia pastoris codon bias and cloned into the expression vector pPICZαA. The recombinant vector was transformed into P. pichia strain X-33 and selected by zeocin resistance. Benchtop fermentation and simple purification strategy were established to purify the rhIL-25 with about 17 kDa molecular mass. Functional analysis showed that purified rhIL-25 specifically bond to receptor IL-17BR and induce G-CSF production in vitro. Further annexin V-FITC/PI staining assay indicated that rhIL-25 induced apoptosis in two breast cancer cells, MDA-MB-231 and HBL-100. This study provides a new strategy for the large-scale production of bioactive IL-25 for biological and therapeutic applications.
    Full-text · Article · Oct 2013 · Applied Microbiology and Biotechnology
  • Source
    • "It was found that treatment of a lung epithelial cell line with IL-25 increased TSLP expression. Furthermore, two important Th2 innate cells, activated eosinophils [53] and basophils [54], secrete bioactive IL-25, which could up-regulate TSLP, indicating cross-talk between immune cells and structural cells related to allergic disease. Interestingly, IL-33 treatment also increased the expression of TSLP and TSLPR in the colons of Trichuris-infected mice [55]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Thymic stromal lymphopoietin (TSLP) has been implicated in the development of allergic inflammation by promoting Th2-type responses and has become a potential therapeutic target. Using in vitro T cell differentiation cultures we were able to validate that TSLP played a more critical role in the early development of Th2 immune responses with less significant enhancement of already developed Th2 responses. Adoptive transfer of naive DO11.10 ovalbumin-specific T cells followed by airway exposure to ovalbumin showed an early impairment of Th2 immune response in TSLP-/- mice compared to wild type mice during the development of a Th2 response. In contrast, transfer of already differentiated Th2 cells into TSLP-/- mice did not change lung pathology or Th2 cytokine production upon ovalbumin challenge compared to transfer into wild type mice. An allergen-induced Th2 airway model demonstrated that there was only a difference in gob5 expression (a mucus-associated gene) between wild type and TSLP-/- mice. Furthermore, when allergic animals with established disease were treated with a neutralizing anti-TSLP antibody there was no change in airway hyperreponsiveness (AHR) or Th2 cytokine production compared to the control antibody treated animals, whereas a change in gob5 gene expression was also observed similar to the TSLP-/- mouse studies. In contrast, when animals were treated with anti-TSLP during the initial stages of allergen sensitization there was a significant change in Th2 cytokines during the final allergen challenge. Collectively, these studies suggest that in mice TSLP has an important role during the early development of Th2 immune responses, whereas its role at later stages of allergic disease may not be as critical for maintaining the Th2-driven allergic disease.
    Preview · Article · Feb 2013 · PLoS ONE
  • Source
    • "Protein & Cell IL-17E (IL-25) IL-25 is a distinct cytokine in the IL-17 family originally identified by sequence homology search (Fort et al., 2001; Lee et al., 2001) and its expression was first characterized in highly polarized Th2 cells, implicating its role in type-2 immune responses (Fort et al., 2001). Latter studies have suggested that IL-25 also expresses in mast cells upon IgE cross-linkage (Ikeda et al., 2003), in alveolar macrophages (Kang et al., 2005), eosinophils (Wang et al., 2007; Dolgachev et al., 2009) and basophils (Wang et al., 2007). We and others also found that IL-25 mRNA expresses in lung epithelial cells treated with allergen (Angkasekwinai et al., 2007) or intestinal epithelial cells exposed to commensal bacteria (Zaph et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The recently identified interleukin-17 (IL-17) cytokines family, which comprises six members in mammals (IL-17A-F), plays essential roles in the host immunity against infectious diseases and chronic inflammatory diseases. The three-dimensional structures containing IL-17A or IL-17F have become available and revealed the unique structural features of IL-17s as well as their receptors. Molecular modeling in this review shows that IL-17s may adopt a "cysteine knot" fold commonly seen in nerve growth factor (NGF) and other neurotrophins. Further modeling analysis unmasks a signature interaction feature of the IL-17F/IL-17RA complex, where a small loop of IL-17RA slots into the deep groove of the interface of IL-17F homodimer. This is quite different from the interaction between the best known four-helix cytokines and their cognate receptors. On the other hand, structure of IL-17A and its monoclonal antibody (CAT-2200) shows that, albeit that the antigenic epitope of IL-17A resides outside of the IL-17A homodimer interface, its physical proximity to the receptor binding groove may explain that antibody blockage would be achieved by interfering with the ligand-receptor interaction. This review is to summarize the advance in understanding the structure and function of IL-17 family cytokines, focusing mainly on IL-17A, IL-17F and IL-17E, in the hope of gaining better knowledge of immunotherapeutic strategies against various inflammatory diseases.
    Full-text · Article · Jan 2011 · Protein & Cell
Show more