26 Multi-site tlierapeutic modaiities for infiammatory bowel diseases - meclianisms of action

Genetic susceptibilities such as the recently identified polymorphisms in the N0D2 gene, as well as environmental factors such as certain bacteria, play a role in the etiology of inflammatory bowel diseases (IBD). Over the years many factors have been identified that contribute to the pathogenesis and the process of inflammation in Crohn's disease (CD) and ulcerative colitis (UC), leading to new therapeutic concepts. Among these contributing factors are cytokines and chemokines, as well as adhesion molecules, which are relevant for the emigration of immune cells into the intestinal mucosa. Mucosal and systemic concentrations of many proinflammatory cytokines are elevated in IBD. An inadequate, and/or prolonged activation of the intestinal immune system plays an important role in the pathophysiology of chronic mucosal inflammation. An 'imbalance' between proinflammatory and anti-inflammatory cytokines has been described in the inflamed mucosa of patients with CD and UC. Many, if not all, of the involved cytokine-mediated pathways have back-up systems. Therefore a therapeutic intervention at a particular, singular, very specific point in the complex network of cytokine and chemokine interactions with each other or their receptors is frequently less likely to be successful than a multi-site targeted anti-inflammatory strategy [1]. Even when the etiology of IBD is completely elucidated a causative therapy might not be possible, and the multi-site anti-inflammatory strategy could still be favorable. Therefore the improvement of 'classic' multi-site targeted anti-inflammatory therapies, as well as the development of new concepts for this approach, is of great importance for the future management of patients with IBD. The improvement of 'classic' concepts and therapies is necessary, as so far no therapeutic strategy has proved successful in all patients. Clinically we observe a 'resistance' of a certain percentage of patients to any particular therapy. An important goal for the future must be a better understanding of mechanisms leading to a relative resistance to classic multi-site anti-inflammatory strategies. This would allow the early identification of patients who are not likely to respond to a treatment modality, would avoid frustrating treatments for the patient and the physician, and could allow more specific concepts for the individual patient. To understand the mechanisms of resistance to a particular multi-site targeted anti-inflammatory therapy we first have to understand the molecular and cellular mechanisms involved in an effective therapy. Important insights into a number of those mechanisms of drug action have been made in the last two decades. A classic example for a multi-site targeting antiinflammatory treatment is therapy with glucocorticoids. Therefore the principles of glucocorticoid therapy, the structure of the effect-mediating receptor, the molecular mechanisms of action and the effects on the cellular levels will be highlighted first in this chapter. The glucocorticoid receptor (GR) is a member of a family of receptors, the so-called nuclear receptor superfamily, which shares structural and functional similarities. Other members of this family are the peroxisome proliferation-activated receptors (PPAR). Ligands to PPARy have recently been shown to be effective in animal models of IBD whereas potential ligands of PPAR-oc were beneficial in a clinical study in active IBD. The inhibition of the proinflammatory transcription factor nuclear factor kappa B ( N F K B ) is likely to be the most important target of glucocorticoid therapy as well as PPAR-mediated effects. Therefore, finally the mechanisms and pathways of N F K B activation, as well as the consequences of N F K B inhibition, will be explained.