Abstracts (complete list) - Wissenschaft Online

Maria Lawrenz, Alexander Visekruna, Thorsten Joeris, Nicole Schmidt, Anjo Kroesen,
Stefan H.E. Kaufmann, Ulrich Steinhoff
Coherence or Coincidence ? - ERK activation and
Immunoproteasomes in Crohn Disease
It is a common hypothesis, that Inflammatory Bowel Disease (IBD), namely Crohn
Disease (CD) and Ulcerative Colitis (UC), results from inappropriate immune response
to normal mucosal microflora. LPS signals via Toll Like Receptor 4 (TLR4) and activates
the TPL2/ERK pathway, a MAPK pathway, that is linked to NF-kB and leads to
production of proinflammatory signals. In this study, we investigated the role of ERK
activation in IBD. Inflamed colonic mucosa from 25 patients with either CD or UC was
analysed by immunohistochemistry and Western Blot. We observed highly activated
ERK in the inflamed colon of patients with CD but not in patients with UC. Furthermore,
in vitro experiments with macrophages from proteasome mutant LMP2 and LMP7 KO
mice revealed a correlation between ERK activation and proteasomal activity. These
findings demonstrate, that high amounts of immunoproteasomes present in inflamed
mucosa of CD patients contribute to activation of the proinflammatory TPL2/ERK
pathway. We suggest that blocking of the immunoproteasome activity by specific
inhibitors is a promising therapeutic intervention strategy in treatment of CD patients.