Therapeutic modulation of signal transduction pathways.

Abstract

Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract, which arises from inappropriate activation of the immune system. The inflammatory response is characterized by overproduction of immune cells, inflammatory cytokines, and tissue-destructive enzymes. IBD is treated with conventional (immunosuppressive) drugs and relatively new therapeutics, such as antiTNF. Anti-TNF medication targets and neutralizes TNF molecules, which are extra cellular mediators of inflammation. Available drugs lighten many of the symptoms of disease. However, they generally do not interfere with the underlying mechanisms, are relatively non-selective and have dose-limiting side effects. Disease relapse remains also a problem with current drug options. For these reasons, new therapeutic modalities are needed in the field of inflammatory pathology. In the last decade, much is learned about underlying pathogenic mechanisms of these diseases and this created new therapeutic options. As a result, attention has shifted toward modulation of intracellular signaling pathways for several chronic inflammatory disorders, such as psoriasis, asthma, pancreatitis, rheumatoid arthritis and IBD. There have been described many signaling pathways, that play a crucial role in inflammatory pathology. These intracellular signaling pathways connect the extracellular environment to the process of gene transcription. We distinguish two major pathways of transcription factor activation, which is shown in Figure 1. 1 The first group consists of latent cytoplasmic transcription factors, which are directly activated upon receptor-ligand interaction. The second group includes intracellular phophorylation cascades. These signaling cascades contain various protein kinases, which can activate downstream target molecules, such as transcription factors.