Glucocorticosteroid therapy in inflammatory bowel diseases: From clinical practice to molecular biology

Abstract

Inflammatory bowel diseases (IBDs), such as ulcerative colitis and Crohn's disease, are chronic pathologies associated with a deregulated immune response in the intestinal mucosa, and they are triggered by environmental factors in genetically susceptible individuals. Exogenous glucocorticoids (GCs) are widely used as anti-inflammatory therapy in IBDs. In the past, patients with moderate or severe states of inflammation received GCs as a first line therapy with an important effectiveness in terms of reduction of the disease activity and the induction of remission. However, this treatment often results in detrimental side effects. This downside drove the development of second generation GCs and more precise (non-systemic) drug-delivery methods. Recent clinical trials show that most of these new treatments have similar effectiveness to first generation GCs with fewer adverse effects. The remaining challenge in successful treatment of IBDs concerns the refractoriness and dependency that some patients encounter during GCs treatment. A deeper understanding of the molecular mechanisms underlying GC response is key to personalizing drug choice for IBDs patients to optimize their response to treatment. In this review, we examine the clinical characteristics of treatment with GCs, followed by an in depth analysis of the proposed molecular mechanisms involved in its resistance and dependence associated with IBDs. This thorough analysis of current clinical and biomedical literature may help guide physicians in determining a course of treatment for IBDs patients and identifies important areas needing further study.

Keywords: Crohn’s disease; Glucocorticoid dependence; Glucocorticoid resistance; Inflammatory bowel diseases; Ulcerative colitis.

Figure 1

Immunologic dynamics and the responses triggered by glucocorticoids in inflammatory bowel diseases. During activation of the immune response in inflammatory bowel diseases (IBDs), the invasion of bacteria and the cytokine cascade triggered by the disruption of the epithelial barrier prompt an inflammatory response in the intestinal mucosa. Among the different cells that participate in the pathology of IBDs, the most important are represented in this diagram. When bacterial organisms interact with dendritic cells (DC), or the intestinal epithelium is disrupted due to an inflammatory response, the production of proinflammatory cytokines and the release of DAMPs (Damaged- Associated Molecular Patterns) such as TNF-α and IL-33, respectively, is elicited. This leads to the infiltration of immune cells such as monocytes which differentiate into proinflammatory M1 macrophages (Mø) and lymphocytes T (T cells), along with mast cell activation. In the presence of glucocorticoids (GCs), the infiltrating monocytes differentiate into a regulatory M2 profile Mø and CD103⁺ DCs. These tolerogenic cells produce anti-inflammatory cytokines, skew the infiltrating naïve T cells toward a T regulatory phenotype, and control the inflammatory response. Also, the action of GCs blocks the production of proinflammatory cytokines by the M1 Mø, T cells and DCs, leading to the healing of the intestinal mucosa. Figure 1 was produced using Servier Medical Art from http://smart.servier.com. TGF-β: Transforming growth factor-β; IL: Interleukin.