Protease-Activated Receptors - Key Regulators of Inflammatory Bowel Diseases Progression

Abstract

The pathogenesis and course of inflammatory bowel diseases are related to both immune system disorders and dysfunction of colon permeability. Moreover, co-existing diseases in patients with Crohn's disease and ulcerative colitis are identified. Currently, there are some therapeutic strategies that affect the function of cytokine/s causing inflammation in the intestinal wall. However, additional approaches which target other components of inflammatory bowel diseases pathogenesis are still needed. Accumulating evidence suggests that proteases and protease-activated receptors seem to be responsible for colitis progression. Experimental and observational studies showed alteration of protease-activated receptors expression in the colon of patients with Crohn's disease and ulcerative colitis. Furthermore, it was suggested that the expression of protease-activated receptors correlated with inflammatory bowel diseases activity. Moreover, regulation of protease-activated receptors seems to be responsible for the modulation of colitis and clinical manifestation of inflammatory bowel diseases. In this review, we present the current state of knowledge about the contribution of protease-activated receptors to Crohn's disease and ulcerative colitis and its implications for diagnosis and treatment.

Keywords: Crohn’s disease; colitis; immune response; inflammatory bowel disease; proteinase-activated receptor; ulcerative colitis.

Figure 1

Impact of PAR₁ on immune response mediated by macrophages and T cells. PAR₁ activation affects IL-23 secretion from macrophages, which induces T cell differentiation.

Figure 2

Significance of PAR₂ in the promotion of fibrosis mediated by myofibroblasts and mast cells. PAR₂ activation induces TNF-α secretion affecting colitis progression and promotion of fibrosis which is regulated by both myofibroblasts and mast cells.

Figure 3

Experimentally proved processes mediated by PARs during the progression of colitis. PARs agonists and neutrophil proteases modulate granulocyte infiltration by MLCK and MLC axis and affect macroscopic damage and colon permeability in an in vivo model of colitis.