Fachbereich Veterinärmedizin



    Regulation der Expression und Sekretion von CEACAM8 durch Granulozyten und deren Rolle auf humanen pulmonalen Epithelzellen (2014)

    Kerneck, Lena (WE 7)
    Berlin: Mensch und Buch Verlag, 2014 — X, 103 Seiten
    ISBN: 978-3-86387-539-8
    URL (Volltext): http://www.diss.fu-berlin.de/diss/receive/FUDISS_thesis_000000097880
    Institut für Mikrobiologie und Tierseuchen

    Robert-von-Ostertag-Str. 7-13
    Gebäude 35
    14163 Berlin
    Tel.+49 30 83 8-518 40/518 43 Fax.+49 30 838 45 18 51

    Abstract / Zusammenfassung

    Bacterial lower respiratory tract infections are characterized by neutrophilic inflammation in human airways. The carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 8 is expressed in and released by human granulocytes and interacts with CEACAM1 expressed on human airway epithelium. Here, we demonstrated that CEACAM8 is released by human granulocytes in response to bacterial DNA in a TLR9-dependent manner, whereas expression of CEACAM8 is regulated in a TLR7/8 dependent manner. Individuals with a high percentage of granulocytes in human bronchial lavage fluid (≥ 15 %) were more likely to have detectable levels of released CEACAM8 in the BALF than those with a no or moderately elevated granulocyte count. Interaction of released CEACAM8 with CEACAM1 expressed on human epithelial cells resulted in reduced TLR2 dependent inflammatory responses. These inhibitory effects were mediated by tyrosine phosphorylation of the immunoreceptor tyrosine-based inhibitory motif (ITIM) of CEACAM1 and by recruitment of the phosphatase SHP-1, which negatively regulated Toll-like receptor 2-dependent activation of the phosphatidylinositol 3-OH kinase-Akt kinase pathway. In conclusion, our results suggest a new mechanism by which granulocytes reduce proinflammatory immune responses in the human airways via secretion of CEACAM8 in neutrophil-driven bacterial infections.
    Thus, the released CEACAM8 might serve as granulocytic resolution-associated molecular pattern interacting with CEACAM1 expressed on human bronchial epithelial cells to avoid hyper-inflammation and to prevent tissue damage.