Insights into the molecular mechanisms and therapeutic implications of interleukin-6 for inflammatory bowel disease

Inflammatory bowel disease (IBD) is a debilitating chronic inflammatory disorder that primarily affects the digestive system, which mainly encompasses Crohn's disease (CD) and ulcerative colitis (UC). Currently, the exact pathogenesis of IBD has not reached a unified conclusion, and most theories attribute it to the result of a combination of genetic, environmental, immunological, and microbial factors. Despite the availability of various treatment options such as biological agents, the management of IBD remains a significant challenge owing to the complicated and heterogeneous nature of this disease. An updated understanding of its pathogenesis and the development of potential molecular targeting agents is required.^[1]

Among the various cytokines implicated in IBD pathogenesis, interleukin-6 (IL-6) has recently been identified as an essential therapeutic target. As an inflammatory marker, IL-6 has been reported to be upregulated in the serum and mucosa of both CD and UC, especially in patients with active disease.^[2] Besides, multiple studies have shown the potential of IL-6 or its receptor as a biomarker for predicting disease activity or prognosis in IBD, which has led to increased interest in understanding the involvement of IL-6 in IBD. Thus, the aim of this article was to provide a current update on the molecular mechanisms and therapeutic implications for targeted therapy of IBD using IL-6-based agents.

Underlying mechanism of IBD pathophysiology: IL-6 is a glycosylated protein comprising 184 amino acids whose signaling pathway exerts a crucial position in various biological processes including immunomodulation and thus contributes to the pathogenesis of many inflammatory disorders. IL-6 signaling could be triggered by classic or trans-signaling pathways, referring sequentially to the process of IL-6 binding to membrane-bound IL-6 receptor (mIL-6R) or soluble IL-6 receptor (sIL-6R), followed by conjugation to the membranous glycoprotein 130 (gp130) and induction of the intracellular signaling [Figure 1A]. Notably, considering that sIL-6R is released from mIL-6R by proteolysis and alternative splicing, there exists a dynamic balance between the classical and trans-signaling. After these processes, downstream cascades, including the JAK/STAT, MAPK, and PI3K/AKT pathways, could be activated, whose corresponding activities rely on different cell types and relative conditions. Since the mIL-6R expressed in specific cell types, just like hepatocytes, leukocytes, and specific epithelial cells, the form of sIL-6R has largely broadened the range of recipient cells, provided that the membranous gp130 is expressed. As for biological functions, the classic signaling mainly exerts protective and regenerative roles (e.g., acute inflammation, anti-bacterial defense, and gastrointestinal regeneration), whereas the trans-signaling pathway has been observed in pro-inflammatory activities, fibrosis and thus contributes to chronic pathological inflammatory conditions including IBD.^[3] As regards mechanisms involving IL-6 in the pathogenesis of IBD, IL-6 has been implicated in various mechanisms [Figure 1B], including regulation of the immune response (e.g., production of pro-inflammatory cytokines, regulation of immune cells, and recruitment of inflammatory cells to the gut), modulation of the intestinal barrier (e.g., regulation of the apoptosis process in intestinal epithelial cells), and interaction with the intestinal microbiota (e.g., influence on microbiome alteration and gut homeostasis).^[4,5]

Figure 1.

(A) Classic signaling and trans-signaling pathways of IL-6. (B) Generation and cellular function of IL-6 in various cells that contribute to the pathogenesis of IBDs. AKT: Serine/threonine kinase; gp130: Glycoprotein 130; IBDs: Inflammatory bowel diseases; IL-6: Interleukin-6; JAK: Janus kinase; MAPK: Mitogen-activated protein kinase; mIL-6R: Membrane-bound interleukin-6 receptor; PI3K: Phosphoinositide 3-kinase; sIL-6R: Soluble interleukin-6 receptor; Th cell: T helper cell; Treg cell: Regulatory T cell.

IL-6 participates in various phases during the trajectory of IBD, including acute inflammation, chronic inflammation, intestinal fibrosis, and carcinogenesis. It has been observed that levels of IL-6 (mainly secreted by endothelial cells, monocytes, and macrophages) and sIL-6R are elevated in active IBD, which implicated the activation of both classic and trans-signaling pathways to induce recruitment and activation of immune cells, release pro-inflammatory cytokines, and express adhesion molecules.^[4,6] Additionally, IL-6 could induce acute-phase reactants like C-reactive protein (CRP) by binding to hepatocytes, possibly contributing to the shedding of IL-6R and increasing of sIL-6R to induce excessive inflammation.^[7] Since inflammation intensifies through an autocrine mechanism, IL-6 has the potential to facilitate the transition from acute to chronic inflammatory phases. In chronic inflammation of IBD, IL-6 promotes the proliferation, recruitment, and resistance to apoptosis of immune cells, as well as induce disruption of gut barrier in which the trans-signaling pathway exert essential roles.^[3,4] In the process of intestinal fibrosis, IL-6 released by various T cells could induce activation of fibroblasts and mesenchymal cells, which further contribute to extracellular matrix production, leading to fibrosis in the intestinal tissue.^[8] However, the exact mechanisms have not been established and further investigations are needed. Furthermore, IL-6 has been identified as a pivotal facilitator of tumorigenesis in colitis-associated cancer, and is predominantly produced by myeloid cells at early stages and T cells at late stages.^[9] IL-6's involvement in the JAK/STAT3 pathway could promote tumor cell proliferation, invasion, and resistance to apoptosis. It could also modulate the tumor microenvironment by inducing sustained production of cytokines and growth factors through immune cells, thus promoting angiogenesis and immune evasion. Meanwhile, negative feedback regulators, like soluble gp130, suppressor of cytokine signaling (SOCS) proteins, and some anti-inflammatory cytokines, could help to fine-tune the IL-6 response to ensure a balanced immune response.^[9]

Altogether, the regulation of IL-6 and its receptors in IBD is complex, involving interactions with multiple cytokines, immune cells, and signaling pathways. The understanding of these processes is still evolving, and ongoing research continues to uncover new insights into its pathogenesis.

Promising surrogate biomarkers: IL-6 has been reported to be upregulated in the serum and mucosa of both CD and UC in comparison to non-IBD individuals, suggesting its potential as a diagnostic marker.^[2,10] Furthermore, serum IL-6 has been identified as a non-invasive surrogate biomarker due to its significant correlation with disease activities as well as histological inflammation, with better performance compared to the erythrocyte sedimentation rate.^[2,10] Besides, multiple studies observed its correlation with CRP, another widely used biomarker in IBD.^[6,10] Furthermore, IL-6 could help to differentiate between responders and non-responders of therapeutic responses, such as in corticosteroid medications for severe pediatric UC.^[11] In addition, higher IL-6 could predict postoperative complications after intestinal surgeries with an area under the curve of 0.71.^[12]

In addition to that, one study observed a significant increase of serum sIL-6R level in IBD patients compared with that in healthy controls, especially among those with active disease.^[6] However, another study observed limited performance of sIL-6R for disease activity, especially in UC.^[10]

As surrogate biomarkers for IBD, IL-6 and its related receptors exhibit different clinical significance. Elevated levels of IL-6 have been associated with disease activity and prognosis in both CD and UC, while studies on sIL-6R are limited and have shown unstable performances, emphasizing the need for further studies.

Novel therapeutic targets: Given the prominent pleiotropy of IL-6 signaling in multiple biological processes, the implications of IL-6-related therapies have been a significant challenge, owing to strivings to suppress the bad while retaining the good. Nowadays, several clinical trials have revealed the therapeutic potential of IL-6-related therapies, which mainly include IL-6 antibodies, IL-6R antibodies, and trans-signaling inhibitors. The clinical trials investigating IL-6 therapies for the treatment of IBD are shown in Supplementary Table 1, http://links.lww.com/CM9/B655.

IL-6 antibodies have shown promising results for the management of several autoimmune conditions, such as rheumatoid arthritis or lupus nephritis, by influencing both classic and trans-signaling pathways. PF-04236921 is a monoclonal antibody toward IL-6. In a phase 2 multicenter open-label trial, 247 CD patients with a suboptimal response following anti-TNFα therapy were enrolled. The results showed that patients treated with 50 mg PF-04236921 had a significant reduction in 8-week and 12-week Crohn's Disease Activity Index scores. Notably, serious adverse events such as intestinal perforation and stenosis could be observed during medication.^[13] Other IL-6 antibodies, like clazakizumab (NCT01545050) or olokizumab (NCT01635621), are also considered in IBD, while the results remain unpublished due to an interruption of the implementation of clinical trials. It should be noted that risks like intestinal perforation, bleeding, and infection are known adverse effects for various IL-6 antagonists, possibly attributable to the interference of intestinal tissue repair and regeneration processes by long-term blockage of IL-6.

Tocilizumab is an antibody targeting both sIL-6R and mIL-6R that inhibit classic as well as trans-signaling pathways and has been applied in the treatment of various inflammatory disorders, such as rheumatoid arthritis, juvenile idiopathic arthritis, and relapsing polychondritis. Notably, several case studies have reported that in patients who suffer from IBD concomitant with these diseases, considerable improvement in intestinal manifestations induced by tocilizumab was observed, while some studies showed insufficient improvement.^[14,15] This raises the question of whether tocilizumab could be investigated for the treatment of IBD. As reported by Ito et al^[16] in 2004, tocilizumab could significantly promote week 12 clinical response and biomarker normalization in patients with active CD. However, no difference was observed in the endoscopic or histological outcomes as well as percentage of clinical remission. For safety analysis, five serious adverse effects requiring hospitalization were observed, including paralytic ileus and gastrointestinal bleeding.^[16] Notably, given that the half-life of tocilizumab is approximately two weeks, this may pose concerns in cases where patients encounter unexpected fluctuations.

Unlike IL-6 or IL-6R antibodies, the trans-signaling inhibitors are antagonists specifically inhibiting the trans-signaling pathway without constraining the classic signaling. Olamkicept is a soluble gp130 Fc targeted for the binding to the IL-6/sIL-6R complex and blocking the subsequent signaling pathways, which has recently been proposed as a potential molecular target for IBD. In a phase 2a prospective trial, nine patients with UC and seven patients with CD were enrolled to receive olamkicept for 12 weeks, and results indicated that among patients treated with olamkicept, 44% achieved a clinical response and 19% achieved a clinical remission. During this 12-week follow-up, no serious gastrointestinal adverse events were observed.^[17] In a recent phase 2b study, 91 patients with moderate-to-severe UC were enrolled to receive olamkicept 600 mg, 300 mg, or placebo for 12 weeks. In addition to the primary outcome of the week-12 clinical response, a total of 25 secondary efficacy outcomes were included in this study, including clinical, endoscopic, histologic, and patient-reported outcomes. Patients treated with 600 mg olamkicept had a superior advantage in clinical remission induction and 16 of 25 secondary outcomes compared to the placebo, indicating its reliable therapeutic efficacy. In this study, olamkicept also exhibited a superior safety profile, with no increased risk of adverse effects compared to the placebo group, suggesting that olamkicept may have potential as a novel treatment option for IBD.^[18]

Perspectives: Overall, IL-6 and related receptors present considerable potential as surrogate biomarkers and therapeutic targets in IBD. For potential as biomarkers, further research is required to fully comprehend IL-6's predicting capacity. As for therapeutic applications, clinical trials of IL-6 and IL-6R antibodies for IBD have shown mixed results with improved efficacy and considerable adverse effects toward the gastrointestinal tract. This is probably because both therapies interfere with the classic as well as the trans-signaling pathways, which are involved in various physiological processes including those exerting protective and regenerative effects in the gastrointestinal tract. In comparison, trans-signaling inhibitors such as olamkicept show comparable efficacy and superior safety for IBD, mainly due to their specific affinity and selectivity toward IL-6 trans-signaling. However, the current studies are still in their early stages, with a relatively small sample size and short-term follow-up in the induction stage; therefore, further research with larger sample sizes is needed to illustrate their long-term efficacy (such as efficacy in inducing endoscopic, histologic remission, and risk of hospitalization or surgery) and safety (rare or unexpected adverse events) during maintenance stage. Future studies should assess the ideal time for therapy initiation, tailoring of therapy to specific subtypes of IBD patients and combining IL-6 blockade with other immunomodulatory or biologics therapies.

In conclusions, IL-6 has emerged as a promising therapeutic molecular target for IBD, which mainly involves pathogenesis through regulating immune response, modulating the intestinal barrier, and interacting with the intestinal microbiota. The current focus on IL-6-related therapies, especially trans-signaling inhibitors, has shown promise for IBD therapy with considerable efficacy and safety. However, the current studies are still in their early stages, and further researches with larger sample sizes and long-term follow-up are warranted to evaluate whether IL-6 targeted therapies will enhance the long-term prognosis and quality of life for IBD patients.

Acknowledgments

We acknowledge Biorender, which is used to create schematic Figures. We also thank Editage Company for English language polishing.

Funding

This study was supported by a grant of from the National Natural Science Foundation of China (No. 82270555).

Conflicts of interest

None.

Supplementary Material

cm9-136-2143-s001.docx ^{(17.4KB, docx)}