Gastroenterology

Gastroenterology

Volume 140, Issue 6, May 2011, Pages 1756-1767.e1
Gastroenterology

Proinflammatory Cytokines in the Pathogenesis of Inflammatory Bowel Diseases

https://doi.org/10.1053/j.gastro.2011.02.016Get rights and content

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.

Section snippets

T-Cell Differentiation Pathways and Gut Inflammation

With the discovery in the late 1980s that T helper (Th) cells differentiate into Th1 and Th2 cells,1 producing different sets of cytokines, it was quickly established that CD differed from UC in that CD seemed to be a Th1 cytokine-mediated disease characterized by increased production of interferon (IFN)-γ, whereas UC seemed to be a Th2 cytokine-mediated disease characterized by increased production of interleukin (IL)-5 production and normal IFN-γ production.2, 3 One caveat, however, was that

Th17 Response in CD Pathogenesis

The concept that CD was an IL-12−driven Th1 inflammation did not remain unchallenged for long: about the time anti−IL-12p40 was shown to be effective in the treatment of CD, a new set of cytokines, the Th17 cytokines (IL-17 and IL-23), was shown to function as effectors in various autoimmune disease models.12, 13, 14, 15 Among the latter was the cell-transfer colitis model in which it was shown that development of colonic inflammation was apparently more dependent on IL-23 than IL-12.16, 17 The

First Wave of Th17 Studies

The initial studies assessing the importance of Th17 responses in experimental colitis and CD used the previously mentioned cell-transfer colitis model. This model consists of inflammation developing in immunodeficient mice (either recombination activating gene [RAG]−deficient or severe combined immune-deficient [SCID] mice) after adaptive transfer of naïve CD4+ T cells (CD45RBhigh T cells) that develop into proinflammatory effector cells in the absence of a mature (CD45RBlow T cells) cell

Th17 Responses Are Essential, But Not Necessarily as Effector Cell Responses

The various studies discussed here appear to offer definitive evidence that at least one major type of experimental colitis, cell-transfer colitis, requires a Th17 response to support development of colonic inflammation. However, before we accept this conclusion we need to consider studies probing the impact of Th17 responses on regulatory T-cell responses. In an initial study of this question, it was shown that the transfer of naïve T cells to immune-deficient (RAG1-deficient) mice also

Concept of Inflammatory Microdomains

So far in our discussion of experimental colitis, we have focused mainly on data from the cell-transfer model of colitis. However, it is not prudent to rely too heavily on this model as a mirror of CD pathogenesis, given the fact that colitis in this model develops under the very special conditions that obtain in an initially lymphopenic host. In addition, genetic studies of CD strongly suggest that unlike the situation in cell-transfer colitis, the T-cell response directly or indirectly

Th1 and Th17 Cytokine Responses in CD

Our evolving knowledge of cytokine production in CD is not unlike that in experimental models of colonic inflammation. Thus, as in the latter case, early studies pointed to the presence of an underlying Th1 response characterized by lamina propria T cells that produced increased amounts of IFN-γ and lamina propria antigen-presenting cells that produced increased amounts of IL-12p70.6 These early findings were corroborated by later studies showing that lamina propria T cells expressed increased

Cytokine Responses in UC

As mentioned at the outset of this review, the cytokines driving UC were identified as having Th2-like characteristics in the initial studies attempting to place it within the Th1/Th2 spectrum. These consisted of lamina propria cells producing increased amounts of IL-5 in the conspicuous absence of increased amounts of IL-4, the more defining Th2 cytokine; hence the descriptive phrase, Th2-like.3 Also absent was any hint of an increased IFN-γ response, ruling out the presence of a Th1-driven

Effector Cytokines “Bridging” the Th1/Th17/Th2 Spectrum—Tumor Necrosis Factor–Like Ligand

The cytokines discussed so far are those that are clearly located somewhere on the Th1/Th17/Th2 spectrum and that are mainly responsible for the distinctive type of inflammation characterizing the form of IBD with which they are associated. There are, however, a well-known group of additional cytokines, such as TNF-α, IL-1β, and IL-6, that are more promiscuous in their function because they are associated with both forms of IBD to a lesser or greater degree.53, 64 These cytokines generally

Anticytokine Agents Likely to Be Useful in the Treatment of IBD

The review of the cytokine responses causing experimental and human intestinal inflammation presented here offers some guideposts relating to the type of new anticytokine therapy likely to be of use in the future treatment of CD and UC. Anti−TNF-α therapy has been and is likely to continue to be a major form of therapy for IBD. However, anti−TNF-α therapy is ineffective in about 50% of initially treated CD patients and becomes ineffective in another 50% of patients over time; thus, the need for

Conclusions

This analysis of the cytokine responses mediating intestinal inflammation in IBD calls attention to the multilayered and complex nature of these responses, which point with ever more clarity to a rational anticytokine therapy of IBD that holds great promise for providing an effective approach to long-term control of IBD inflammation.

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    Conflicts of interest The authors disclose no conflicts.

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