Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases

Abstract

The cytokine responses characterizing the inflammatory bowel diseases are the key pathophysiologic elements that govern the initiation, evolution, and, ultimately, the resolution of these forms of inflammation. Studies during the last 2 decades now provide a detailed (but not yet complete) picture of the nature of these responses. The first tier of cytokine responses are governed by the T-cell differentiation patterns dominating the disease. In Crohn's disease, the major cytokines arise from T-helper cell (Th) 1 and Th17 CD4(+) T-cell differentiation and consist of interferon-γ and interleukin (IL)-17/IL-22 generated by these types of differentiation. The relative importance of these cytokines to Crohn's inflammation is still unclear, although evidence is mounting that interferon-γ is primus inter pare (first among equals). In contrast, in ulcerative colitis, a Th2-like differentiation process is paramount, which results in expansion of natural killer T cells producing IL-13 (and perhaps IL-5). These disease-specific cytokine patterns give rise to a second tier of cytokines that span the Th1/Th17-Th2 divide and act as upstream facilitators and downstream mediators of inflammation. These cytokines include the well-known tumor necrosis factor-α, IL-1β, IL-6 triumphirate, as well as a more recently studied cytokine known as TL1A (tumor necrosis factor-like ligand). In this review, we will explore this cytokine landscape with the view of providing an understanding of how recent and future anticytokine therapies actually function.

Figure 1. The Basic Dichotomy of Cytokine Function In IBD

Whereas Crohn’s disease and ulcerative colitis are both forms of inflammatory bowel disease (IBD) and exhibit overlapping genetic profiles, these disease are characterized by very different T cell responses. Crohn’s disease is driven by a Th1/Th17 response in which IL-12 and IL-23 cytokines play key roles. Ulcerative colitis, in contrast is driven by a Th2-like response in which NKT cells producing IL-13 (and IL-5) is the major response. In addition, in both forms of IBD cytokines that have functions both “upstream” and “downstream” of these basic cytokines also play important inflammatory roles.

Figure 2. Regulatory Mechanism Initiated by the Th17 Response

The role of the Th17 response in CD is under intense investigation. It is gradually emerging that in this disease this response may be more important in the regulation of the inflammation than in its induction. In this diagram the Th17 response (depicted by the cells shown in blue) generate cells producing IL-17 and IL-22, the latter a cytokine clearly known to ameliorate gut inflammation. This response depends on the production of IL-23 which also inhibits regulatory T cell (Treg) generation (depicted by the cells shown in red) and thus counter-acts the inhibitory effect on Tregs on both Th1 (IFN-γ) and Th17 (IL-17) pro-inflammatory responses. In contrast, IL-17 interaction with IFN-γ-producing cells (depicted by the cells shown in green) via an IL-17 receptor inhibits generation IFN-γ producing cells. Thus, the Th17 response is both permissive and inhibitory of the Th1 response, probably at different phases of the inflammatory cycle.

Figure 3. Inflammatory Micro-Environments Characterizing CD

There is considerable evidence that Th1 and Th17 responses are in an uneasy state of co-existence (See Figure 2). In this figure the concept is put-forward that such co-existence is minimized by the fact that Crohn’s inflammation consists of innumerable micro-environments, each exhibiting a progression of inflammatory patterns. In the initial and most intense phase of the inflammation, Th1 responses predominate; at this point, production of IL-23 in a nascent Th17 response inhibits Treg generation and feeds the inflammation. In a later phase a mixed T cell response prevails in which the Th1 response is still predominant but is now moderated by a Th17 response producing both IL-17 (which inhibits IFN-γ T cells) and IL-22.

Figure 4. The Pathogenesis of Ulcerative Colitis

Inflammation in ulcerative colitis is initiated by glycolipid antigen(s) rising from either the microbiota or epithelial cells acted upon by microbiota. These antigens are presented to NKT cells in the context of CD1 on the surface of epithelial cells or dendritic cells and the NKT cells so stimulated act as effector cells mediating disease. Resultant epithelial cell damage and ulcer formation is caused by the cytotoxic activity of the NKT cells which recognize epithelial cells bearing antigen-loaded CD1 as targets or by IL-13 which has been shown to cause epithelial cell apoptosis and loss of epithelial barrier function; in addition, IL-13 enhances NKT cell cytotoxity.

Figure 5. TL1A Function

TL1A is a TNF-family member that acts exclusively via DR3. It’s pro-inflammatory function bridges the Th1/Th17-Th2 dichotomy in that it enhances both types of T cell responses. As shown in this Figure, Th1 or Th17 differentiation results in T cells that express DR3 (the TL1A receptor) and are then subject to TL1A co-stimulation, the latter necessary for optimal proliferative and cytokine responses. Th2 cells are co-stimulated in a similar manner (not shown). TL1A has other effects such as those of Tregs that are not depicted here which may also contribute to inflammation.