Cytokines in inflammatory bowel disease

Journal name:
Nature Reviews Immunology
Volume:
14,
Pages:
329–342
Year published:
DOI:
doi:10.1038/nri3661
Published online

Abstract

Cytokines have a crucial role in the pathogenesis of inflammatory bowel diseases (IBDs), such as Crohn's disease and ulcerative colitis, where they control multiple aspects of the inflammatory response. In particular, the imbalance between pro-inflammatory and anti-inflammatory cytokines that occurs in IBD impedes the resolution of inflammation and instead leads to disease perpetuation and tissue destruction. Recent studies suggest the existence of a network of regulatory cytokines that has important implications for disease progression. In this Review, we discuss the role of cytokines produced by innate and adaptive immune cells, as well as their relevance to the future therapy of IBD.

At a glance

Figures

  1. Conceptual framework for the pathogenesis of IBD.
    Figure 1: Conceptual framework for the pathogenesis of IBD.

    Genetic and environmental factors induce impaired barrier function in the intestinal mucosa. Initiating triggers may involve infections in some patients. Altered barrier function subsequently induces the translocation of commensal bacteria and microbial products from the gut lumen into the bowel wall, which leads to immune cell activation and cytokine production. If acute mucosal inflammation cannot be resolved by anti-inflammatory mechanisms and the suppression of pro-inflammatory immune responses, chronic intestinal inflammation develops. In turn, chronic inflammation may cause complications of the disease and also tissue destruction, which are both driven by mucosal cytokine responses. DC, dendritic cell; IBD, inflammatory bowel disease; NSAIDs, non-steroidal anti-inflammatory drugs; TReg cell, regulatory T cell.

  2. Cytokines in the pathogenesis of IBD.
    Figure 2: Cytokines in the pathogenesis of IBD.

    In patients with inflammatory bowel disease (IBD) and in experimental mouse models of colitis, pro-inflammatory and anti-inflammatory cytokines have been shown to be produced by various cells of the mucosal immune system in response to environmental triggers, such as commensal microorganisms. In particular, dendritic cells (DCs), neutrophils, macrophages, natural killer (NK) cells, intestinal epithelial cells (IECs), innate lymphoid cells (ILCs), mucosal effector T cells (T helper 1 (TH1), TH2 and TH17) and regulatory T (TReg) cells produce cytokines in the inflamed mucosa. The key transcription factors and cytokines produced by T helper cell subsets in IBD-affected mucosa are shown. The balance between pro-inflammatory and anti-inflammatory cytokines in the mucosa regulates the development and potential perpetuation of mucosal inflammation in patients with IBD. The dashed arrow indicates that ILCs, which produce cytokines that are involved in intestinal inflammation, may respond to IL-18. GATA3, GATA-binding protein 3; IL, interleukin; RORγt, retinoic acid receptor-related orphan receptor-γt; TGFβ, transforming growth factor-β; TNF, tumour necrosis factor.

  3. Central role of tumour necrosis factor in the pathogenesis of IBD.
    Figure 3: Central role of tumour necrosis factor in the pathogenesis of IBD.

    In inflammatory bowel disease (IBD), increased amounts of soluble and membrane-bound tumour necrosis factor (TNF) are produced by various immune and stromal cell populations, such as macrophages, dendritic cells (DCs), effector T cells, adipocytes and fibroblasts. TNF has been shown to exert various pro-inflammatory functions in the inflamed mucosa in IBD. In particular, TNF induces hypervascularization and angiogenesis, augments pro-inflammatory cytokine production by macrophages and T cells, causes barrier alterations and promotes cell death of intestinal epithelial cells (IECs) and Paneth cells. TNF also promotes tissue destruction by increasing the production of matrix metalloproteinases (MMPs) by myofibroblasts and drives T cell resistance to apoptosis via the induction of TNF receptor-associated factor 2 (TRAF2) and the activation of nuclear factor-κB (NF-κB). TNF-specific antibodies may alleviate disease by simultaneously suppressing several pro-inflammatory pathways in patients with IBD. IL, interleukin; MLCK, myosin light chain kinase; RIPK, receptor-interacting protein kinase; TIMP1, tissue inhibitor of matrix metalloproteinases 1.

  4. The crucial role of cytokines and epithelial cells on the battlefield: mucosal healing and cancer in IBD.
    Figure 4: The crucial role of cytokines and epithelial cells on the battlefield: mucosal healing and cancer in IBD.

    Intestinal epithelial cells (IECs) are exposed to numerous pro-inflammatory and anti-inflammatory cytokines during chronic intestinal inflammation in inflammatory bowel disease (IBD). These cytokines are produced by cells in the local microenvironment and by IECs themselves. Local cytokine responses have major effects on mucosal healing and cancer development in patients with IBD. The cellular sources of key cytokines and their signalling cascades that regulate IEC survival, cell death and proliferation are shown. In the context of mucosal healing in ulcers (left), green boxes indicate beneficial effects of cytokines, whereas red boxes highlight pathogenic effects of cytokines. In colitis-associated cancer (right), blue boxes indicate pro-tumour effects of cytokines. DC, dendritic cell; IFN, interferon; IL, interleukin; ILC, innate lymphoid cell; TH cell, T helper cell; TNF, tumour necrosis factor.

  5. Cytokine signalling in IBD.
    Figure 5: Cytokine signalling in IBD.

    Cytokine signalling pathways and intracellular Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signalling cascades in mucosal immune cells are shown. In IBD, the activation of certain STATs in mucosal T cells results in augmented cytokine production. Several pro-inflammatory cytokines have been implicated in IBD pathogenesis and are potential targets for therapy. Antibodies targeting soluble tumour necrosis factor (TNF) and membrane-bound TNF (such as infliximab, adalimumab, certolizumab pegol and golimumab) are routinely used in the clinic. In addition, cytokine blockers (for example, tocilizumab, which targets interleukin-6 (IL-6) and ustekinumab, which targets the p40 subunit of IL-12 and IL-23) have been recently tested in clinical studies. In addition, inhibitors of JAK and STAT signalling (for example, the JAK3 and JAK1 inhibitor tofacitinib, which blocks IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 signalling) have yielded promising results in clinical trials. Future therapy of IBD may also use bispecific tetravalent dual variable domain IgG (DVD-Ig) antibodies. Finally, the identification of specific cytokines and cytokine expression patterns that are unique to certain subsets of patients with IBD may open new avenues for future personalized medicine for these disorders. βc, cytokine receptor common subunit-β; γc, cytokine receptor common subunit-γ; gp130, IL-6R subunit-β; LIFR, leukaemia inhibitory factor receptor; OSMR, oncostatin-M-specific receptor subunit-β; TRAF2, TNFR-associated factor 2; TYK2, tyrosine kinase 2.

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Affiliations

  1. Department of Medicine 1, University of Erlangen-Nürnberg, Kussmaul Campus for Medical Research, 91054 Erlangen, Germany.

    • Markus F. Neurath

Competing interests statement

M.F.N. has served as an adviser for MSD Pharmaceuticals, AbbVie, Pentax Corporation and Giuliani Pharma.

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  • Markus F. Neurath

    Markus F. Neurath received his M.D. from the University of Mainz, Germany, and his postdoctoral training from the National Institutes of Health, Maryland, USA. After serving as a physician scientist and professor at the University of Mainz, he was visiting professor at the Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. He then joined the University of Erlangen-Nürnberg, Germany, where he is currently Director of the Medical Clinic 1 (Gastroenterology, Pneumology, Endocrinology). His research focuses on the role of cytokine signalling in inflammatory bowel diseases and colon cancer, as well as the pathways that regulate T cell death. More recently, his group has investigated the role of epithelial cells and innate immunity in intestinal diseases.

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