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What is the role of cytokines and chemokines in IBD?

Cytokines and chemokines are small (4–15 kDa), inducible, proinflammatory, and immune-regulatory proteins that play a central role in the development and homeostasis of the immune system. A network of cytokines has been extensively investigated in inflammatory bowel disease (IBD) and an imbalance of proinflammatory and counterregulatory molecules has been demonstrated in both Crohn’s disease (CD) and ulcerative colitis (UC) tissues. The proinflammatory cytokines interleukin (IL)-1 , IL-6, IL-8, IL-18, IFN, and TNFare produced in excess,1 while the immunosuppressive IL-10 is reduced and the inhibitory activity of TGF1 signaling is paradoxically inefficient. Both the excess of proinflammatory cytokines and the relative inefficiency of counterregulatory molecules are required for maintaining, amplifying, and perpetuating chronic inflammation in IBD.2,3 Within the cytokines network in IBD different secretory patterns and pathways have been identified. A general consensus has been reached for a predominant role of Thelper1 (Th1) cytokines in CD. IL-12, the major Th1-inducing cytokine produced by locally active macrophages, is overexpressed and the IL-12-induced IFNoverproduction in the mucosa determines the downstream release by macrophages of proinflammatory cytokines.4 Evidence also indicates that in the gut mucosa the IL-12-induced Th1 polarization can be expanded by other locally induced cytokines, such as IL-15 and IL-18. IL-21, a newly T-cell-derived cytokine of the IL-2 family, has been recently associated with IBD. The expression of this molecule is enhanced in IBD, in direct correlation with disease activity, and a functional evaluation suggests that IL-21 contributes to stabilize the Th1 phenotype at the site of inflammation.5 Mucosal immune response in UC differs from that occurring in CD. Several observations indicate a predominant humoral immunity characterized by a high level of IgG (marked increase of IgG1 subclass antibodies, capable of the complement activation) released by mucosal plasma cells. T cells isolated from colonic mucosa of UC patients release high IL-5 and IFN, while IL-4 is relatively low. All these data indicate an “atypical” Th2 response. This view is also supported by the recent suggestion that the Th2 cytokine IL-13 is produced by UC lamina propria T cells affecting epithelial tight junctions, apoptosis, and cell restitution.6 Recently, the traditionally Th1/Th2 dichotomy has been revisited for the identification of a new distinct Th cell subset, the IL-17-producing (Th-17) cells that appear to play a decisive role in various immune-inflammatory diseases and antibacterial responses.7 Th17 cells, characterized by the expression of the transcription factor ROR t and secretion of IL-17, may play a decisive role in the production of chemokines that facilitate the recruitment of neutrophils into inflamed intestine, as well as they could coordinate gut inflammation by inducing the synthesis of other inflammatory molecules, such as IL-6 and TNF, or extracellular matrixdegrading enzymes.7,8 Th17 cells appear to be predominant in the gut of patients with CD and patients with UC9,10 and accumulating evidence suggests also that Th17 cells have a pathogenic role in experimental models of IBD.11,12 IL-21 and IL-23 are upregulated during these experimental models and several functional data indicate these cytokines, in concert with TGF, play an important role in sustaining pathogenic Th17 cell responses in the gut.13 The end result of the various pathways within the cytokine network in IBD is the promotion and induction of tissue-damaging mediators. IL-1 and TNFpromote the release of nitric oxide, prostacyclin, and platelet-activating factor. In addition, different cytokines induce the expression of chemokines and/or adhesion molecules on the vascular endothelium—thus favoring the recruitment of new inflammatory cells—and also stimulate gut fibroblast to synthesize matrix metalloproteinases.1,14 Chemokines are important in both homing of leukocytes under physiological conditions and determining activation, recruitment, and retention of leukocytes along a chemotactic gradient. In chronic inflamed IBD tissue this function is enhanced, contributing to a massive infiltrate of immune cells. Over 40 human chemokines are now known and classified into 4 subgroups: CC chemokines, largely involved in the recruitment of lymphocytes and dendritic cells, and CXC chemokines, more strongly implicated in neutrophil and monocyte recruitment, are the 2 major subgroups. In both forms of IBD the mucosal expression of several chemokines such as CCL2 (MCP-1), CCL3 (MIP-1 ), CCL4 (MIP-1 ), CCL5 (RANTES), CCL8 (MCP-2), and CXCL’s 1–3, CXCL8 (IL-8) and CXCL10 (IP-10) has been shown to be upregulated during the active phases.15,16 CCL20 (MIP-3 ) is a recently described CC chemokine produced by gut epitheFrom the Gastroenterology Unit, Department of Internal Medicine, University Tor Vergata, Rome, Italy. Copyright © 2008 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.20677 Published online in Wiley InterScience (www.interscience.wiley.com).