Current research focus of the group
We teach the complex mechanisms of action and the evidence-based application of all approved anti-inflammtory drugs (see tabel above).In contrast, our research is focussed on specific unknown aspects of signal transduction mediated by interleukin(IL)-1 (but also by TNF and by some forms of stress). In particular we are interested in understanding how IL-1 regulates gene expression.We study these problems in cell culture models using biochemical, molecular biology, cell biology and bioinformatics methods.

Schematic representation of IL-1 signalling pathways that are studies by us at present

IL-1 receptors (IL-1R) are expressed ubiquitiously and constitutively on most cells of the body. The IL-1R is a heterodimer. The agonistisc ligands (IL-1 a und IL-1 b ) are rapidly secreted by cells of the innate immune system (macrophages, monocytes). Binding of IL-1 a or IL-1 b to the IL-1R induces protein:protein interactions involving receptor proxinal adaptor proteins and protein kinases that are not shown here including MYD88, IRAK1-4 and Tollip. Within 2-10 minutes this results in formation of another oligomeric signalling complex that contains the adaptor protein TRAF6, the protein kinase TAK1 and the TAK1-binding proteins TAB1-TAB3. TRAF6 also possesses ubiquitin ligase activity. This activity generates cross-linked ubiquitin chains which stabilize TAK1-TAB1-3 complexes and provide docking surfaces for further protein recruitment and signal transduction (for an example see, pdf. ) . TAK1 and TAB1-TAB3 are phosphorylated in an IL-1-dependent manner, the role of these phosphorylations ist still not clear. For an experiment showing rapid IL-1-induced activation of the TAK1-TAB2 complex see here ( pdf. ). Subsequently and further downstream the MAP kinases JNK, p38 and ERK (not shown) and the NF-kappaB signaling pathway are activated (for an example see here, pdf. ). JNK phosphoryates and activates the transcription factor AP-1including ist subunit c-Jun ( pdf. ). Cells deficient in JNK or c-Jun show severe defects in IL-1-induced gene expression ( pdf. ). Regulation of the transcription factor NF-kappaB is very complex. In its inactive form, NF-kappaB is kept in the cytoplasmn, after activation by IL-1 it translocates to the nucleus and binds to enhancer and promoter regions of numerous inflammatory genes. For an example of IL-1-dependent recruitment of NF-kappaB to the IL-8 Promoter see here ( pdf. ) . For an overview on IL-8 gene regulation see here ( pdf., pdf. ). For an experiment by which we tried to stduy IL-1-induced gene expression at the genome-wide level see here ( pdf., pdf. ). Recently we were able to show that JNK/c-Jun and NF-kappaB assemble into specific chromatin-associated protein:DNA complexes. Within these complexes we also found histone deacetylases such HDAC3. The precise role of these complexes for regulation of IL-1-induced cellular responses has not yet been worked out. Presumably, at this level of nuclear signalling a sophistcated transmission of IL-1-signals is generated to activate many genes in parallel. This apparently involves rearrangement of chromatin structure.

Abbreviations: IL-1R, interleukin-1 receptor; TRAF, TNF-receptor-associated factor; TAK1, TGF b -activated protein kinase 1; TAB1/2, TAK1-binding protein1/2; MKK4/7, MAP kinase kinase 4/7; JNK, Jun-N-terminal kinase; NF-kappaB, nuclear factor kappa B; HDAC, histon deacetylase; Pol II, RNA polymerase II; PIC; preinitiation complex; P, phosphorylation; Ac, acetylation.

Current questions and projects ....