Sites of inflammation are characterized by an influx of inflammatory cells that drive a high metabolic turnover in an environment of fading oxygen availability. Oxygen concentrations in non-diseased tissues vary between 4- 15% under physiological conditions and easily become hypoxic (O2 < 5%) during chronic but also acute inflammatory process. Many bacterial pathogens survive well and even grow under anaerobic conditions, thus host-defense mechanisms must be adapted to function effectively when oxygen tension is low. To compensate for environmental changes in O2 supply, host cells get under the control of “hypoxia-inducible factors (HIF)”, of which HIF-1 regulates most of the hypoxia-dependent genes involved in cell metabolism, apoptosis and innate immunity. However, there´re some good indications that suggest differences in inflammation progression with respect to the surrounding oxygen concentrations. The hypoxia-inducible factor-1 is a ubiquitously and constitutively produced transcription factor composed of an oxygen-labile α-subunit and an oxygen-resistent β-subunit, with the latter being identical with the aryl hydrocarbon nuclear translocator. HIF-1α possesses two central oxygen dependent degradation domains (ODDs) and two transactivation domains. In the presence of O2, human HIF-1α is hydroxylated at the proline residues Pro-402 and Pro- 564 within the ODDs, immediately captured by the von Hippel-Lindau protein, and degraded via the E3 ubiquitin ligase pathway. Interestingly, obligate intracellular chlamydiae (C. pneumoniae, C. trachomatis) evolved strategies to directly interact with the oxygen-sensing mechanisms of infected cells to meet their needs on energy and nutrients and actively manipulate cell survival and proliferation. During the mid- to late phase of the infection (48- 72h p.i.), chlamydiae secrete the chlamydial protease-like activity factor (CPAF) into the cytosol of infected host cells. CPAF interaction with HIF-1α results in degradation of the transcription factor, which facilitates intracellular growth and progeny of chlamydiae under hypoxic conditions. The precise compartmentalization and function of CPAF as well as its substrate specificity in Chlamydia- infected host cells still has to be determined.
Looking on host defense mechanism to suppress intracellular growth of chlamydiae under hypoxia we found, that antibacterial properties of type II interferon were dramatically down regulated. Hypoxic loss of IFN-γ function was due to diminished activation of the classical Jak-Stat pathway and reduced activity of the indoleamine 2,3 dioxygenase (IDO). Taken together, there is good evidence that characteristics of host-pathogen interactions differ fundamentally in environments of reduced oxygen availability, and more precisely reflect inflammatory process in vivo.
Prof. Dr. med. J. Rupp
Siegrid Pätzmann (MTLA)
Anke Hellberg (MTLA)
Dr. Thomas Hellwig-Bürgel, Institut für Physiologie
Prof. M. Klinger, Institut für Anatomie