| Lung is a mucosal surface that constantly interacts with environmental antigens including innocuous antigens, immunogenic allergens and infectious microorganisms. Alveolar macrophages (AMs) play an important role in regulation of innate immune response to environmental antigens. Dysregulation of innate immune response results in inflammatory diseases such as allergic asthma. The purpose of this dissertation was to understand role of AMs in proinflammatory and anti-inflammatory response associated with allergic asthma, by investigating macrophage migration inhibitory factor (MIF) and Cholesterol 25-hydroxylase (CH25H) expressed in AMs.;MIF was hypothesized to induce proinflammatory response by inducing gene expression, activation of AMs and recruiting immune cells Lung histology, IgE ELISA, microarray experiments showed lower leukocyte infiltration and lower inflammation. Cellular infiltration and serum IgE level was lower in Mif-/-, compared to WT. Microarray experiment indicated that MIF may not regulate gene expression directly. Weaker inflammation was not in a single cell level, as assessed by bone marrow-derived macrophages (BMM). From the surface marker analysis of AMs, lower inflammation of Mif-/- may be mediated in the tissue level.;CH25H plays important roles in regulating lipid metabolism, gene expression and immune activation. Microarray experiments showed CH25H was highly induced in allergic airway inflammation. To identify the regulation of CH25H expression, bone marrow-derived dendritic cells (BMDC) and BMM were used. TLR3- and TLR4 agonists induced transcription of Ch25h, which was mediated by the production of type I interferons (IFN) and signaling through IFNalphaR and JAK/STAT1, as assessed by using the related gene-deficient mice. Interestingly, the expression of CH25H in allergic airway inflammation was mediated by IL-4 and IL-13 in a STAT6-dependent manner.;To explore the effect of CH25H expression in dendritic cells, 25HC was treated CD4+ T cells and resulted in inhibition of T effecter activation but not Treg activation, as shown in transcription and flow cytometric analyses. 25HC-treated BMDC inhibited CD4+T cell activation and proliferation in antigen presentation. Ch25h-expressing RAW264.7 cell lines were able to induce cell death of activated CD4+ T cells. These data suggested that CH25H expression in inflamed lungs could have immunoregulatory role in adaptive and innate immunity, through 25HC. |
