Opposing Functions of Classic and Novel IL-1 Family Members in Gut Health and Disease

Abstract

In addition to their well-established role(s) in the pathogenesis of gastrointestinal (GI)-related inflammatory disorders, including inflammatory bowel disease (IBD) and inflammation-associated colorectal cancer (CRC), emerging evidence confirms the critical involvement of the interleukin-1 (IL-1) cytokine family and their ligands in the maintenance of normal gut homeostasis. In fact, the paradigm that IBD occurs in two distinct phases is substantiated by the observation that classic IL-1 family members, such as IL-1, the IL-1 receptor antagonist (IL-1Ra), and IL-18, possess dichotomous functions depending on the phase of disease, as well as on their role in initiating vs. sustaining chronic gut inflammation. Another recently characterized IL-1 family member, IL-33, also possesses dual functions in the gut. IL-33 is upregulated in IBD and potently induces Th2 immune responses, while also amplifying Th1-mediated inflammation. Neutralization studies in acute colitis models, however, have yielded controversial results and recent reports suggest a protective role of IL-33 in epithelial regeneration and mucosal wound healing. Finally, although little is currently known regarding the potential contribution of IL-36 family members in GI inflammation/homeostasis, another IL-1 family member, IL-37, is emerging as a potent anti-inflammatory cytokine with the ability to down-regulate colitis. This new body of information has important translational implications for both the prevention and treatment of patients suffering from IBD and inflammation-associated CRC.

Keywords: IL-1 family of cytokines; Toll/IL-1 receptor family; colitis; inflammation-associated colon cancer; inflammatory bowel disease; intestinal fibrosis; intestinal homeostasis; mucosal wound healing.

Figure 1

Receptor-ligand pairing of IL-1 family members. Productive pairings of ligand, binding receptor, and accessory protein for the IL-1 (upper left), IL-18/IL-37 (upper right), IL-33 (lower left), and IL-36/IL-38 (lower right) systems. The overall bioactivity of IL-1 family agonists is dependent on the prevalent isoform and receptor binding domain/accessory protein present on effector cells. Promiscuous receptor/co-receptor binding of agonists and antagonists imply that IL-1 family members cannot be considered in isolation, but in the context of other IL-1 family members that can influence their overall integrative effects and impact on disease pathogenesis.

Figure 2

Common signaling pathway for Toll/IL-1R (TIR) family members. TLRs possess significant homology to IL-1R family members and share a similar cytoplasmic TIR domain with receptors of IL-1, IL-18, IL-33, and IL-36. The TIR domain is essential for recruitment of cytoplasmic adapter proteins, which in turn initiates downstream signaling cascades. PAMPS, pathogen-associated molecular patterns.

Figure 3

Role of IL-1 family members in the gut mucosa and potential therapeutic strategies to restore intestinal homeostasis. The effects of the same IL-1 family member can vary, and are often dichotomous, depending on the cell source, phase of disease (early vs. late), and inflammatory state (acute vs. chronic) of the host. IECs and APCs are critically involved in maintaining gut homeostasis, but also in triggering gut inflammation. icIL-1Ra, IL-18, and IL-33 released by IECs, together with sIL-1Ra, IL-37, and low levels of IL-1β produced by APCs, and sIL-1RII shed by macrophages, promote physiological inflammation, and homeostasis. Chronic intestinal inflammation results when this balance is disrupted, often changing the cellular sources and absolute levels of IL-1 family members. Based on this imbalance, therapeutic strategies aimed at modulating levels of IL-1 family members can be designed to reestablish gut health.

Figure 4

Role of IL-1 family members in colon cancer. Similar to chronic intestinal inflammation characteristic of IBD, an imbalance between protective and pathogenic IL-1 family members is also an important mechanism leading to intestinal tumorigenesis and the development of GI-related cancers. In fact, IL-1 cytokines play an important role in sustaining tumor growth by stimulating growth factor production and modulating host immune responses against tumor cells. While the roles of classic IL-1 family members, such as IL-1 and IL-18, have been firmly established, only speculation can be made on other, newer IL-1 family members, such as IL-33, IL-36, and IL-37.

Figure 5

Working hypothesis summarizing opposing functions of IL-1 family members within the gut mucosa. The balance between pro-inflammatory and protective cytokines is crucial for the maintenance of gut homeostasis. Damage to the epithelium (e.g., ulcer formation) and other pro-inflammatory stimuli, including PAMPs derived from luminal antigens and the local intestinal microflora, induce the expression of IL-1 family members that are subsequently released by necrotic IECs as potential alarmins (e.g., IL-33 and IL-1α). Depending on the cellular source and presence of receptor-bearing effector cells, IL-18 can possess very different functions within the gut mucosa. IL-33 may also act on various immune cell populations, including macrophages, and T- and B-cells, eliciting a pro-inflammatory response and promoting Th2 immunity. Concomitantly, IL-33 can also induce epithelial proliferation and repair, and overall wound healing by acting directly or indirectly on IECs and SEMFs. Alternatively, chronic mucosal damage, granulomatous inflammation, and dysregulated activation of mesenchymal cells, such as SEMFs and fibroblasts, can lead to fibrosis and the formation of intestinal fibrotic lesions. Therapeutic interventions should consider all of the aforementioned processes and whether targeting specific IL-1 family members may be more efficacious during active disease vs. maintaining remission.