Itation: Cell Death and Illness (2013) 4, e786; doi:ten.1038/cddis.2013.327 2013 Macmillan Publishers Restricted
Itation: Cell Death and Disease (2013) 4, e786; doi:ten.1038/cddis.2013.327 2013 Macmillan Publishers Restricted All rights reserved 2041-4889/ amyloid A inhibits dendritic cell apoptosis to induce glucocorticoid resistance in CD4 T cellsJL Ather1, KA Fortner2, RC Budd2, V Anathy3 and ME Poynter*,Mediators made by the airway epithelium manage the activation, recruitment, and survival of pulmonary dendritic cells (DC) that present antigen to CD4 T cells through the genesis and exacerbation of allergic asthma. The epithelial-derived acute phase protein, serum amyloid A (SAA), induces DC maturation and TH17 polarization. TH17 responses are related with serious types of allergic asthma which can be poorly controlled by corticosteroids. We sought to identify no matter whether SAA would boost the survival of DC throughout serum starvation and could then contribute for the improvement of a glucocorticoid-resistant phenotype in CD4 T cells. Bone marrow-derived dendritic cells (BMDC) that have been serum starved in the presence of SAA were protected from activation of caspase-3 and released much less lactate dehydrogenase. In comparison with untreated serum-starved BMDC, remedy with SAA downregulated mRNA expression in the pro-apoptotic molecule Bim, elevated production from the pro-survival heat shock protein 70 (HSP70), and induced secretion of pro-inflammatory cytokines. SAA-treated BMDC that had been serum starved for 48 h remained capable of Bcr-Abl drug presenting antigen and induced OTII CD4 T cells to IP web secrete IL-17A, IL-17F, IL-21, IL-22, and IFNc inside the presence of ovalbumin. IL-17A, IL-17F, IL-21, and IFNc production occurred even when the CD4 T cells were treated with dexamethasone (Dex), whereas glucocorticoid therapy abolished cytokine secretion by T cells cocultured with untreated serum-starved BMDC. Measurement of Dex-responsive gene expression demonstrated CD4 T cells as the target of glucocorticoid hyperresponsiveness manifest as a consequence of BMDC stimulation by SAA. Lastly, allergic airway illness induced by SAA and antigen inhalation was unresponsive to Dex remedy. Our outcomes indicate that apo-SAA affects DC to both prolong their viability and improve their inflammatory possible below apoptosis-inducing circumstances. These findings reveal mechanisms through which SAA enhances the CD4 T-cell-stimulating capacity of antigen-presenting cells that might actively participate in the pathogenicity of glucocorticoid-resistant lung disease. Cell Death and Disease (2013) four, e786; doi:ten.1038/cddis.2013.327; published online five SeptemberSubject Category: ImmunityDendritic cells (DC) function each as innate responders that take up antigen and secrete acute inflammatory mediators, and as modulators of your adaptive response, directly affecting the phenotype of effector and helper T cells.1 Under regular conditions, a naive DC that encounters a harmless antigen won’t mature, and can as an alternative undergo apoptosis; likewise, mature DC treated with Toll-like receptor (TLR) agonists possess a `molecular timer’ that limits their lifespan and, subsequently, their ability to present antigen to T cells.4 DC that presented both antigen as well as the apoptotic trigger Fas ligand (FasL) to T cells were able to induce T-cell hyporesponsiveness and ameliorate the development of allergic airway disease,5 suggesting that interference using the standard apoptotic pathway for the duration of DC cell interactions could lead toinappropriate and prolonged antigen presentation and an exacerb.