The mucosal inflammatory response. Cytokines and chemokines

Abstract

Cytokines and chemokines play an important role in inflammatory bowel disease (IBD) pathogenesis, as demonstrated by the efficacy of cytokine-targeted immunomodulatory therapy in treating IBD. The precise etiology of IBD is unknown, but disease pathogenesis clearly involves genetic, immunologic, and environmental factors. The current hypothesis for IBD etiology suggests that the disease is initiated and perpetuated by a dysregulated immune response to an unknown environmental antigen in a genetically susceptible host. A working hypothesis for the pathogenesis of Crohn's disease, the most debilitating form of IBD, is depicted in Fig. 1. In order to maintain gut homeostasis, the normal mucosal immune system must maintain a delicate balance between a network of proinflammatory and/ or inductive cytokines and anti-inflammatory and/or regulatory cytokines. During bacterial invasion the proinflammatory and inductive type I T-helper cell (Thl)-polarizing cytokines exert pleiotropic effects upon release from antigen-presenting cells (macrophages, dendritic ceUs, etc.) in the intestinal mucosa. Proinflammatory cytokines (i.e. interleukin [IL]-1, IL-6, and tumor necrosis factor [TNF]) activate immune cells in the lamina propria and stimulate intestinal epithelial cells (lEC) and macrophages to produce chemokines which, when secreted, estabUsh a chemotactic gradient across the intestinal mucosa, promoting leukocyte recruitment and extravasation across the intestinal endothelium. Meanwhile, Thlpolarizing cytokines (i.e. IL-12, IL-18, TNF) released from antigen-presenting cells (primarily macrophages) induce activation of naive intraepithelial and lamina propria T lymphocytes and Thl differentiation. These activated Thl cells release Thl cytokines (i.e. IL-2, interferon gamma [IFN-y], and lymphotoxin [LT]), which further perpetuate inflammatory and delayed hypersensitivity immune responses in the gut. In the normal gut mucosa this proinflammatory/ inductive immune response is kept in balance by a network of anti-inflammatory and regulatory cytokines. Regulatory cytokines (i.e. IL-10, IL-4, IL-5, IL-13, and transforming growth factor beta [TGFp]) are derived from many cellular sources within the intestine, including macrophages as well as type IIThelper (Th2) cells and type I T regulatory (Trl) cells. Along with anti-inflammatory cytokines (i.e. IL-1 receptor antagonist [IL-lra] and IL-11) derived primarily from lEC and macrophages, these Th2 cytokines serve to counterbalance the proinflammatory effects of Thl-mediated immune responses. For unknown reasons, patients with IBD cannot maintain normal gut homeostasis. An understanding of the cytokine network and its role in promoting IBD pathogenesis is a crucial step toward finding a cure for this devastating disease. This chapter provides an overview of the cytokines and chemokines that have been implicated in IBD, with specific focus on what is known about each cytokine in relation to IBD pathogenesis and treatment.