Gene therapy targeting nuclear factor-kappaB: towards clinical application in inflammatory diseases and cancer.

Nuclear factor (NF)-kappaB is regarded as one of the most important transcription factors and plays an essential role in the transcriptional activation of pro-inflammatory cytokines, cell proliferation and survival. NF-kappaB can be activated via two distinct NF-kappaB signal transduction pathways, the so-called canonical and non-canonical pathways, and has been demonstrated to play a key role in a wide range of inflammatory diseases and various types of cancer. Much effort has been put in strategies to inhibit NF-kappaB activation, for example by the development of pharmacological compounds that selectively inhibit NF-kappaB activity and therefore would be beneficial for immunotherapy of transplantation, autoimmune and allergic diseases, as well as an adjuvant approach in patients treated with chemotherapy for cancer.

Mice overexpressing p40 in lungs have reduced leucocyte influx and slightly impaired resistance during tuberculosis.

Interleukin (IL)-12 (p70) is a heterodimeric cytokine composed of p40 and p35, that plays a major role in the protective immune response to Mycobacterium tuberculosis. To define the role of p40 in lungs during pulmonary M. tuberculosis infection we generated transgenic (Tg) mice overexpressing p40 under control of the surfactant protein C promoter.

Differential role of interleukin-6 in lung inflammation induced by lipoteichoic acid and peptidoglycan from Staphylococcus aureus.

Lipoteichoic acids (LTA) and peptidoglycans (PepG) are major components of the cell walls of gram-positive bacteria that trigger inflammatory responses in vitro. To study the in vivo effects of LTA and PepG from Staphylococcus aureus in lungs and to determine the role of interleukin (IL)-6 herein, these compounds were intranasally administered to IL-6 gene deficient (IL-6(-/-)) and wild type (IL-6(+/+)) mice. In IL-6(+/+) mice, LTA and PepG induced acute pulmonary inflammation in a dose-dependent way, characterized by neutrophilic influx and IL-6 production in the bronchoalveolar lavage fluid.

Cytokines in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic disease characterized by synovial inflammation that leads to the destruction of cartilage and bone. In the last decade, there was a lot of successful research in the field of cytokine expression and regulation. It has become clear that pro- and anti-inflammatory cytokines, derived predominantely from cells of macrophage lineage, play a major role in the initiation and perpetuation of the chronic inflammatory process in the RA synovial membrane.