IL-17 in pancreatic disease: pathogenesis and pharmacotherapy

Abstract

Increasing evidence highlights the role of the interleukin (IL)-17 family in pancreatic diseases. IL-17A induces acinar cell injury directly, recruits neutrophils, and cooperates with other inflammatory factors to exacerbate pancreatic inflammation. It also triggers islet β-cell apoptosis and nitric oxide-dependent cytotoxicity, thus aggravating islet inflammation. IL-17A seems to have different roles in pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancer (PC). IL-17A participates in the progression of acinar-ductal metaplasia (ADM) and PanIN, but not related to the characteristics of PC stem cells and the overall survival of patients. Acting similar to IL-17A, IL-17B accelerates the invasion and metastasis of PC, and predicts prognosis of PC and the therapeutic effect of gemcitabine. Herein, we review the current understanding of the pathogenesis of IL-17 in pancreatitis, type 1 diabetes mellitus (T1DM), and PC, as well as potential pharmacotherapy targeting IL-17 and its receptors in pancreatic diseases. The findings summarized in this article are of considerable significance for understanding the essential role of IL-17 in pancreatic diseases.

Introduction

Pancreatitis, diabetes mellitus, and pancreatic cancer (PC) are common and widespread diseases occurring in pancreatic tissue, which bring a heavy burden to the economy and society [1]. Pancreatitis is often accompanied by disturbances in glucose metabolism [2]. Also, pancreatitis and diabetes are both high-risk factors for PC [3]. Due to the presence of the same pancreatic tissue, there may be some mutual influence between the pathogenesis of pancreatitis, diabetes, and PC [4,5]. The interleukin (IL)-17 family is a multi-functional cytokine with six subtypes (IL-17A to IL-17F), which is well known for its pivotal role in psoriasis and rheumatoid arthritis [6-8]. In recent years, accumulating numbers of publications have reported the role of IL-17 in the pathogenesis of autoimmune diseases [9-11], inflammation [12], cancer [13], or even COVID-19 [14]. As to the pancreatic disease, IL-17A can directly damage acinar cells, recruit neutrophils and other immune cells, thus aggravating pancreatitis [15]. Meanwhile, T helper cell 17 (Th17) and their secreted cytokine IL-17 mediate autoimmune injury of islet β cells in type 1 diabetes mellitus (T1DM) [16]. IL-17A, 1L-17B, and IL-17E all participate in the pathogenesis of PC [17,18]. Moreover, the interactions between the IL-17 family members result in complex regulatory functions. In this article, we provide an overview of the biological properties of IL-17 and its function in the pathogenesis of pancreatic diseases, as well as targeted pharmacotherapy modalities for IL-17 and its receptors.

The origin and classification of IL-17 family

The IL-17 family is composed of six homologous dimeric proteins (IL-17A-F) and a heterologous dimeric protein (IL-17A/F) [11,19] (Figure 1). As the broadly most studied cytokine of the IL-17 family, IL-17A was first discovered by Rouvier in 1993 and initially named CTLA-8 [20,21]. Concurrently, IL-17A is the characteristic marker of Th17 cells and exerts a crucial role in the pathogenesis of autoimmune diseases, inflammation, and cancer [22]. Relatively speaking, IL-17B is an emerging area for IL-17 family research, which is widely expressed in a variety of tissues, including the stomach, pancreas, and intestine, and closely related to the pathogenesis of gastric cancer, PC, and other malignant tumors [23-26]. Whereas, IL-17C is mainly expressed by the oral mucosal epithelium, cutaneous mucosal epithelium, and airway mucosal epithelium [27,28]. By recruiting neutrophils into the tumor microenvironment (TME), IL-17C promotes the growth and proliferation of lung cancer [29]. Currently, a minority of literature has reported that IL-17D, of which receptor remains unknown, possibly plays an immune regulatory role in tumors and infections [30-32]. IL-17E is widely distributed and induces Th2 type immune response [33,34]. In Addition, IL-17A and IL-17F are located on the same chromosome with 55% homology in amino acid sequence [35,36]. Also, they are usually produced by the same types of cells, forming homodimeric or heterodimeric proteins to exert similar functions [11]. However, compared to IL-17A, IL-17F is a weaker inflammation inducer, and its triggered signal intensity and induced downstream gene activation response are significantly lower than IL-17A [23,37]. In brief, IL-17A-F constitute the IL-17 family and play different roles in immunity, inflammation, and tumorigenesis.

Figure 1.

IL-17 family, IL-17 receptors and signal transduction. The IL-17 family is composed of six homologous dimeric proteins (IL-17A/A, B/B, C/C, D/D, E/E, F/F) and a heterologous dimeric protein (IL-17A/F). Mechanistically, IL-17 conducts signals by binding to the specific IL-17 receptor, which is characterized by a fibronectin type III domain in the extracellular portion and a conserved SEFIR protein domain in the cytoplasmic tail that recruits NF-κB activator 1 to deliver IL-17-dependent immune responses. Specifically, IL-17RA/RD acts only as a receptor for IL-17A/A, while IL-17RA/RC can act as a co-receptor for IL-17AA, AF, FF. Except for the unknown receptors of IL-17B/B and D/D, the receptors of IL-17C/C and IL-17E/E are IL-17RA/RE and IL-17RA/RB, respectively. SEFIR, Sef/IL-17R; Act1, NF-κB activator 1.

IL-17 receptors

IL-17 cytokines need to bind to specific IL-17 receptors to transmit upstream signals. The IL-17R family is a single transmembrane protein consisting of five receptor subunits from IL-17RA to IL-17RE with a size of 499-866 amino acid sequences (Figure 1) [23,37]. Characteristically, IL-17R contains a fibronectin type III domain and a conserved Sef/IL-17R (SEFIR) protein domain, which resides in the extracellular and cytoplasmic tail, respectively [38]. By binding to specific IL-17R receptors, IL-17 transmits upstream signals to the downstream. In this process, nuclear factor kappa-B (NF-κB) activator 1 (Act1), which recognizes the SEFIR region of the IL-17 receptor, is recruited into the IL-17R complex and transmits IL-17-mediated inflammatory responses [39,40]. Mechanistically, IL-17 binds to the IL-17 receptor not in the simple pattern of IL-17A corresponding to IL-17RA, but in homodimers or heterodimers formed between IL-17 receptors, just as IL-17A binds to heterodimers formed by IL-17RA and IL-17RC [7]. Furthermore, in light of the current findings, IL-17RA is likely to be a common receptor shared by the cytokines of the IL-17 family [41]. That is, IL-17RA may form heterodimer receptor complexes with IL-17RC, IL-17RB, IL-17RE, and IL-RD, which bind to the corresponding ligand IL-17 to transmit upstream signals [19,36,39]. IL-17RA and IL-17RC constitute a receptor complex that is the receptor of a homodimer or heterodimer protein composed of IL-17A and IL-17F [36]. IL-17RD, known as an orphan receptor, has recently been demonstrated to form a heterodimer with IL-17RA. IL-17RD/RA receptor complex only binds to IL-17A homodimer, but not to IL-17A/F or IL-17F/F, acting as the second functional receptor for IL-17A to mediate the downstream inflammatory response of IL-17A [42]. Also, IL-17RA may form a heterodimer with IL-17RB, acting as the receptor of IL-17E (IL-25) to transmit signals [38]. Similarly, IL-17RA also binds to IL-17RE to form a heterodimer that serves as a specific receptor for IL-17C [35,43]. Besides IL-17RA, a cytokine receptor may bind to different cytokines, such as IL-17B and IL17E, both bind to IL-17RB. Interestingly, IL-17B participates in the pathogenesis of gastric cancer and PC by binding to the corresponding receptor IL-17RB [23,25,26]. Although the mechanism of signal transduction between IL-17 and the IL-17 receptor is becoming more apparent as research progresses, the receptor for IL-17D remains unknown. Therefore, these complex regulatory interactions between IL-17 and its receptors still need further study to elaborate.

IL-17 and pancreatitis

AP is a widespread acute gastrointestinal disease that occurs in exocrine acinar cells of the pancreas [44]. Cholelithiasis, hyperlipidemia, alcohol, and other pathogenic factors induce the premature of trypsinogen and intracellular activation of NF-κB signal pathway in pancreatic acinar cells, which ultimately lead to pancreatic inflammation [45]. With advances in various minimally invasive surgical therapies and organ function support therapies, the incidence of complications and mortality rates have decreased. However, the prevalence of pancreatitis is still increasing year by year in the world [46-48]. Meanwhile, since the mechanism of AP remains obscure, apart from aggressive fluid resuscitation and organ function support therapies in the early stages of the disease, there is no specific drug for the treatment of AP [49]. Moreover, immunotherapeutic targeting IL-17A have achieved better clinical outcomes in psoriasis and immune arthritis [50,51]. IL-17 has attracted many investigators’ attention in the pathogenesis of autoimmune diseases, inflammation, and tumors. Also, IL-17A has been revealed to closely related to the pathophysiology of pancreatitis in recent years. In the article below, we therefore address the pathogenesis of IL-17 in AP (Figure 2).

Figure 2.

Schematic diagram of IL-17 in the pathogenesis of pancreatitis and T1DM. In acute pancreatitis, the inflamed pancreas and activated inflammatory monocytes/macrophages release cytokines to recruit naive CD4+ T cells, which then differentiate into Th17 cells and γδT cells to secrete IL-17A. IL-17A subsequently causes acinar cells injury and stimulates acinar cells to secrete inflammatory cytokines and chemokines, which further promote the recruitment and differentiation of immune cells such as neutrophils, monocytes/macrophages, and ultimately amplifying the inflammatory cascade of acute pancreatitis. In type 1 diabetes, IL-17A secreted by TH17 cells, CD8+ T cells, and γσT cells induces pancreatic β-cell apoptosis, up-regulate the expression of iNOS mRNA and protein in pancreatic islet cells, and causing NO-dependent pancreatic β-cell toxicity, aggravating the damage of pancreatic β-cells in type 1 diabetes. Th17, T helper cell 17.

IL-17A is a pivotal pro-inflammatory cytokine produced by Th17 cells and γδT cells, which is the first member discovered among the IL-17 family [21]. The level of serum IL-17A in patients is significantly increased after the onset of AP, which can be used as a valuable prognostic index to judge its severity [52-54]. Additionally, IL-17A can also be used as a prognostic factor for length of stay, organ dysfunction, and mortality in severe AP patients treated with continuous blood purification [55]. Although IL-17A was associated with the initiation of systemic inflammatory response syndrome in AP, a study in 2018 revealed that IL-17A was not the cause of sepsis after pancreatic infection and necrosis in the second stage of severe AP [56]. Mechanistically, IL-17A interacts with acinar cells, infiltrating immune cells, and other cytokines to aggravate the progression of AP and related complications [57]. In AP, injured acinar cells and recruited inflammatory monocytes/macrophages release IL-1β and IL-6 to recruit naïve CD4+ T cells into pancreatic tissue, which then differentiate into Th17 cells to produce IL-17 that acts on IL-17 receptor-positive cells to release various inflammatory mediators that exacerbate pancreatitis [15,58]. IL-17A receptor is a heterodimer complex that consists of IL-17RA and IL-17RC and broadly expresses in acinar cells, stellate cells, monocytes/macrophages, neutrophils, and other immune cells. Notably, IL-17A analogues may damage acinar cells directly and stimulate these cells to secrete inflammatory cytokines and chemokines, thereby amplifying the cascade of AP [15]. However, Leppkes et al. [59] found that IL-17A could not directly act on acinar cells but recruit neutrophils in a PADI4-dependent manner to induce AP. Though most people believe that IL-17A is primarily released by Th17 cells in AP, a recent study has proved that in the model of AP induced by Coxsackie B, IL-17A is mainly produced by V γ 4 γ δ T cells, while CD4+ Th17 cells produce a small portion [60]. By activating the IL-23/IL-17/neutrophil axis, IL-17A exacerbates virus-induced AP [60].

Since IL-17A exacerbates AP through different mechanisms, the pharmacological blockade of the IL-17 signaling pathway may exert a partial effect on the treatment of AP. Silencing the S100A9 gene, for example, blocks the IL-17 signaling to inhibit the secretion of inflammatory cytokines during AP [61]. In AP, CD4+ T cells are recruited to the inflamed-pancreas, resulting in an increased proportion of Th17/Treg, which indirectly accelerates the secretion of pro-inflammatory cytokine IL-17. Wang et al. [58] elucidated that miR-155 is closely related to the differentiation of CD4+ T cells to Th17 cells. Pre-treating isolated human CD4+ T cells with a miR-155 inhibitor might reduce the conversion of CD4+ T cells to Th17 cells, thereby reducing the secretion of IL-17 and relevant pathological damage of pancreas. Of note, a recent study showed that functional IL-17 receptors are also existed in pancreatic stellate cells [62]. By activating ERK1/2 and up-regulating fibrogenesis genes, IL-17A fosters pancreatic fibrosis. Anti-IL-17A antibody may reduce the effect of IL-17A on pancreatic stellate cells and attenuate pancreatic fibrosis in CP [62]. In a word, IL-17A released by Th17 and γδT cells stimulate acinar cells, stellate cells, and various immune cells to augment the release of inflammatory cytokines, recruiting more immune cells, and ultimately causing inflammatory cascades in pancreatitis. Reducing the release of IL-17A or specifically blocking IL-17A receptors in different ways may offer a potential treatment for pancreatitis.

IL-17 and T1DM

The pancreas has both endocrine and exocrine functions. The inflammation that occurs in acinar cells is pancreatitis, while the inflammation occurring in pancreatic endocrine β cells is diabetes. Various pathological factors lead to the activation of auto-reactive T cells, B lymphocytes, and the innate immune system, which synergistically destroy insulin-producing β cells to develop T1DM [63-65]. Islet β cell injury, insulin deficiency, and diabetic symptoms are distinctive clinical manifestations of T1DM [16]. In T1DM, islet β cells and immune cells play complex regulatory roles through cytokines and chemokines [66,67]. The increase of pro-inflammatory cytokines (interferon-γ, IL-6, and tumor necrosis factor-α (TNF-α)) and the decrease of anti-inflammatory cytokines (transforming growth factor-β (TGF-β), IL-10, and IL-33) lead to the imbalance of inflammatory factors, causing pancreatic β-cell damage [66]. Studies of the autoimmune diabetic mouse (NOD mice) reveals that the pathogenesis of T1DM is associated with the expressions of Th17 cells and IL-17 [68]. IL-17, secreted by Th17 cells, CD8+ T cells, and γσT cells, plays an essential regulatory role through IL-17RA and RC receptor complex ubiquitous on the surface of islet cells [69,70] (Figure 2). Firstly, IL-17A aggravates islet inflammation by directly inducing apoptosis of β-cell and increasing cytokines and chemokines locally [71]. Secondly, concentrations of IL-17A are elevated in the peripheral blood of children. Through interacting with IFN-γ and IL-1β, it synergistically induce inflammation and apoptosis in human pancreatic islet cells [72]. Next, IL-17A may trigger the upregulation of inducible nitric oxide synthase (iNOS) mRNA and protein expression in the MIN6β cell line and cause nitric oxide-dependent toxicity [73]. Finally, immune cells can also infiltrate into exocrine glands such as salivary glands and lacrimal glands of NOD/LtJ mice to produce IL-17, which destroys local glandular tissue and aggravates T1DM-associated Sjogren’s syndrome [74]. However, there still exist some contrary or contradictory findings of the function of IL-17A and Th17 cells in T1DM. In initially diagnosed T1DM patients (less than six months), the expression of IL-17RA in CD3+ and CD4+ T cells are surprisingly lower than that in healthy controls [75]. That means, the IL-17A pathway possibly does not activate in the peripheral blood of newly diagnosed T1DM patients.

As T1DM is associated with immune damage of pancreatic islet β cells, modulating the immune response to mitigate islet cell injury is the primary goal for the treatment of T1DM [65]. Owing to the involvement of IL-17A in pancreatic β-cells immune injury, drugs that reduce the secretion of IL-17A or block its interaction of IL-17A to the receptor may have the efficacy of treating T1DM (Table 1). A recent study showed that saffron extract could significantly reduce the production of IL-17A in pancreatic cell populations, increase the levels of IL-10 and TGF-β, thereby treating T1DM [76]. For the fact that IL-17A is primarily secreted by Th17 cells in T1DM, pharmaceuticals that diminishes the number of Th17 cells may alleviate the inflammation of islet β cells by diminishing the secretion of IL-17A. At present, a widely used anti-diabetic medicine, dipeptidyl peptide-4 (DPP-4) inhibitors, may attenuate autoimmune injury and improve the function of TIDM islet β cells by inhibiting the conversion of CD4+ T cells into Th17 phenotype and the release of IL-17A [77,78]. In addition, both Th17 cells and Treg cells derived from the differentiation of naïve CD4+ T cells, which may convert to each other under the stimulation of different cytokines owing to the plasticity of CD4+ T cells [79]. Interestingly, when the researchers transplant Th17 cells to the NOD mice, Th17 cells transform their phenotypes into Th1 cells that predominantly expressed IFN-c [80]. Therefore, the subtypes of CD4+ T cells can transform from each other under the regulation of the immune environment of T1DM. In diabetes and other autoimmune diseases, Th17 cells secrete IL-17A/F and IL-22 to trigger autoimmunity and inflammation, while Treg cells maintain immune homeostasis by secreting anti-inflammatory cytokines including TGF-β and IL-10 [81]. There is a disbalance of Th17 and Treg cells in diabetes. Restoring the disproportionality may be an effective strategy to prevent and treat diabetes and its complications [82,83]. By increasing the ratio of Treg/Th17 cells in pancreatic lymph nodes and the spleen, Cordyceps Sinensis, which is a parasitic fungus originated from traditional Chinese medicine, can delay the onset and reduce the severity of T1DM [84]. Human gingival mesenchymal stem cells (GMSCs), as a novel source of stem cells, have also been used to treat T1DM. Mechanistically, GMSCs injected intraperitoneally can migrate to the pancreas and local lymph nodes, release juxtacrine or paracrine factors to promote the proliferation of CD4+ Tregs, and suppress the secretion of IL-17A by T cells. Thus, alter the imbalance between Tregs and T effector cells and ultimately improve streptozocin-induced islet cell damage [85]. Notably, in contrast to IL-17A, IL-17E may inhibit the formation of Th17 cell populations in response to GAD65 antigen in islet β cells, and increase the number of Treg cells [86]. Also, as an immunomodulatory molecule, IL-12 can suppress the activity of Th17 cells by inducing the secretion of IFN-γ, thereby reducing the production of IL-17 and preventing diabetes [87]. Theoretically, retinoid-related orphan nuclear receptor γt (RORγt) is a crucial transcription factor to induce naïve CD4+ T cells differentiation into Th17 cells [88]. Moreover, inactivated autoreactive T cell vaccine (TCV) is an effective treatment for autoimmune diseases. Wang et al. [89] demonstrated that TCV could diminish the differentiation of Th17 cells by inhibiting the signal transduction of RoRγt and phosphorylation of transcriptional activator 3, which in return decrease the production of IL-17 and IL-23.

Table 1.

Overview of therapeutic drugs for T1 diabetes mellitus targeting IL-17

Drugs	Mechanism	Application	Species	Ref.
Saffron extract	Reduce the production of IL-17	Streptozotocin-induced T1DM	Mice	[76]
	increase the levels of IL-10 and TGF-β
GMSCs	Induce the expression of CD4+ Treg subpopulation	Streptozotocin-induced T1DM	Mice	[85]
	Suppress the differentiation of naive CD4+ T cells into Th17 and Th1 cells
DPP-4 inhibitor	Inhibit Th17 phenotype and IL-17 production in CD4+ T cells	Peripheral blood mononuclear cells	Human	[77,78]
T-cell vaccine	Inhibit retinoic acid-related orphan receptor γt signal transduction and STAT3 phosphorylation, Reducing the production of pancreatic infiltrating lymphocytes IL-17 and IL-23	Multiple streptozotocin-induced T1DM	Rat	[89]
Cordyceps Snensis	Increase the ratio of regulatory T cells/Th17 cells	Autoimmune diabetes	Mice	[84]
Recombinant IL-25	Reduce T cell infiltration around islets	Autoimmune diabetes	Mice	[86]
	Increase the proportion of regulatory T cells
IL-12	Induce IFN-g secretion	Autoimmune diabetes	Mice	[87]
	Inhibit the expression of Th17 cell-associated proinflammatory cytokines
Combination therapy with T-cell receptor antibodies and cytokine antibodies against IL-17A or/and IL-6	Relieve the autoimmune injury of pancreatic islet β mediated by T cell receptor lymphocytes and the inflammatory response around the islet	Insulin-dependent diabetes	Rat	[67]

Abbreviations: T1DM, T1 diabetes mellitus; GMSCs, gingival mesenchymal stem cells; DPP-4, dipeptidyl peptide-4; TGF-β, transforming growth factor-β; Th17, T helper cell 17; IFN-γ, interferon-γ.

Though anti-IL-17A antibodies achieved remarkable achievements in the treatment of psoriasis, psoriatic arthritis, and ankylosing spondylitis [9,51]. The application of anti-IL-17A specific antibody alone has demonstrated no affection on the progression of diabetes [86]. The reason may be that neutralization of IL-17A by antibodies only eliminates effector molecules, but be more conducive to the secretion of IL-17A by Th17 cells due to the corresponding negative feedback. Interestingly, anti-IL-17A or anti-IL-6 antibody combined with anti-T cell antigen receptor (TCR) can significantly decrease anti-TCR-mediated lymphocyte infiltration around islets, reduce pro-inflammatory cytokines secretion, restore islet β-cell function and treat diabetes [67]. Overall, IL-17A participates in the pathogenesis of T1DM by directly damaging islet cells and synergizing with other cytokines. The specific immune responses of IL-17A and IL-17A receptors in T1DM still need to be confirmed in further study. Therapeutic approaches that regulate the balance of Th17/Treg cells, inhibit the secretion of IL-17 or neutralize IL-17A with antibodies, have shown better therapeutic prospects.

IL-17 and pancreatic cancer

PC is a highly malignant digestive system cancer, which was predicted to become the second cause of cancer-related deaths in the United States in 2030 [90,91]. Its early clinical symptoms are insidious, and the 5-year survival rate is less than 3% [92]. Due to the complex and dense TME, PC exhibits significant resistance to existing treatment options, including chemotherapy, radiotherapy, and targeted therapy [93]. TME is an unique environment that facilitates tumor growth and immune escape by interacting with immune cells and the surrounding pancreatic stroma [93,94]. Among the TME, IL-17 exerts a complex interaction with cells and cytokines adjacent to the tumor, participating in a series of processes including chronic pancreatitis, acinar-ductal metaplasia, PanIN, and advanced tumor progression (Figure 3) [17,95,96].

Figure 3.

Schematic diagram of the role of IL-17 in the pathogenesis of acinar duct metaplasia, pancreatic intraepithelial neoplasia, and pancreatic cancer. IL-17A stimulates REG_3β that is a pancreatitis mediator in pancreatic epithelial cells to promote acinar-ductal metaplasia and the progression of Pan IN. By increasing the expression of DCLK1, IL-17A can also regulate the stem cell characteristics of pancreatic intraepithelial tumor cells. The elevated IL-17A in the pancreatic tumor microenvironment recruit neutrophils by releasing specific cytokines and chemokines, exclude cytotoxic CD8+ T cells from the tumor, thus maintaining an immunosuppressive microenvironment. IL-17B recruits neutrophils, lymphocytes by activating the ERK1/2 signaling pathway, ultimately promoting the invasion and metastasis of pancreatic cancer. In contrast, IL-17E plays an anti-tumor effect by activating B lymphocytes in pancreatic cancer. ADM, Acinar duct metaplasia; Pan IN, Pancreatic intraepithelial neoplasia; Th17, T helper cell 17.

Accumulating evidence suggests that IL-17 and Th17 cells are significantly elevated in the peripheral blood of patients with PC, and positively correlated with the stage of the tumor [97,98]. Indeed, due to the plasticity of T cells, Th17 cells and Treg cells can transform into each other under the influence of local microenvironment at different stages of PC, manifesting as characteristic changes of cytokines. For instance, Liu et al. found that Treg cells decreased, while IL-17A expression increased in peripheral blood of patients with PC in stable and remission stages [99]. Nevertheless, in the peripheral blood of patients with unresectable advanced PC, Treg cells were elevated, and IL-17A expression decreased. Furthermore, the number of Th17 cells and IL-17A in the TME of PC was significantly higher than that in peripheral blood and paracancerous tissues of the same patient [97]. Although the expression of IL-17 and Th17 cells in tumor tissue and peripheral blood is abnormal, the underlying molecular mechanism has not been elucidated. IL-17 secreted by Th17 and γσT cells in the TME exerts effects on the IL-17RA of PanIN epithelial cells, promoting the expansion of stroma around the tumor, and accelerating the initiation and progression of PanIN [100]. Also, IL-17A may stimulate the pancreatitis mediator REG3-β in KrasG12D mutated pancreatic epithelial cells and activate the gp130-JAK2-STAT3-dependent pathway, promoting acinar-ductal metaplasia and PanIN development [101]. By increasing the expression of doublecortin-like kinase 1, POU class 2 homeobox 3, aldehyde dehydrogenase 1A1, and IL-17RC, IL-17A may regulate the stem cell properties of PanIN cells [96]. A recent study showed that dendritic cells in the TME of PC could induce naive CD4+ T cells to differentiate into Th17 cells by secreting cytokines, including IL-23, IL-6, and TGF-β, thereby promoting the release of IL-17A and tumor progression [102]. Interestingly, these elevated IL-17A in the TME of PC also recruits neutrophils and triggers neutrophil extracellular traps, which exclude cytotoxic CD8+ T cells from the tumor, thus maintaining the immunosuppressive microenvironment [103]. However, another study recently reported that IL-17A was not associated with stem cell characteristics of PC cells and overall survival in patients with PC [104]. Therefore, in terms of the studies currently involved, IL-17A seems to play different roles in the progress of PanIN and PDAC progression, and its intrinsic mechanism needs to be confirmed by further research.

IL-17B/IL-17RB signaling plays a similar role as IL-17A/IL-17RA in the pathogenesis of PC. IL-17B may bind to the IL-17B receptor of tumor cells, promote the expression of chemokine C-X-C motif chemokine ligand (CCL)1, IL-8, CCL20, and trefoil factor 1 by activating the ERK1/2 signaling pathway, thus recruiting neutrophils, lymphocytes, and vascular endothelial cells, ultimately promoting the invasion and metastasis of PC [25]. Concurrently, the expression of IL-17RB can also be used to predict the prognosis of patients with resectable PC, and the adjuvant therapy effect of gemcitabine [105]. Interestingly, IL-17E plays an antitumor role by activating the NF-κB signaling pathway in B lymphocytes, increasing the levels of IL-5 and eosinophils in serum. In addition, IL-17E could exert a more substantial antitumor effect in combination with chemotherapeutic drugs or immunotherapeutic drugs [106]. The dense fibrous connective tissue around PC and the complex TME infiltrated by various immune cells lead to different clinical effects of immunotherapy in different stages of PC [90,93]. The neutralizing antibody of IL-17A may block the initiation of PC induced by KRAS, but does not interfere with the progression of PC [101,104]. Notably, an anti-IL-17RB monoclonal antibody can block tumor metastasis and improve survival rate in mice with PC xenotransplantation, thus showing good therapeutic potential [25,26]. The combined administration of anti-IL17/IL17R and PD-1 or CTLA4 antibodies markedly reduces the size of pancreatic tumors by activating CD8+ T cells and alleviates the drug resistance brought by the above-mentioned drugs alone, demonstrating a better clinical application value [103]. Recently, some excellent articles focus on the mechanism of intestinal microorganisms in pancreatic diseases. On the one hand, pancreatic acinar cells secrete massive digestive enzymes and antimicrobial peptides from the pancreatic juice into the intestine, regulating the intestinal microbial population and the immune barrier function [107,108]. On the other hand, intestinal microbes and their products interact with the host’s immune system through pattern recognition receptors to promote the progression of gastrointestinal tumors [109]. Oral administration of broad-spectrum antibiotics to remove intestinal microorganisms may reduce the number of immune cells secreting IL-17 and increase the number of T cells secreting antitumor factor interferon-γ, thus inhibiting the growth of PC [110]. Therefore, the regulation of intestinal flora has become a new strategy of tumor immunotherapy. In a word, with the further investigation of IL-17 family members and their receptors in the pathogenesis of PC, pharmacotherapy targeting IL-17 may contribute to improving the therapeutic effect of PC.

Conclusions and prospects

In conclusion, we have discussed the IL-17 family and their receptors in the development of pancreatitis, T1DM, and PC. The application of drug therapy targeting IL-17 in pancreatic diseases is also summarized. However, the current reports on IL-17 in pancreatic diseases mainly focus on IL-17A, with a few involving IL-17B and IL-17E. The role of other IL-17 family members and their receptors in pancreatic diseases remains unknown. Due to the dysfunction of multiple organs involved in pancreatitis and diabetes, as well as the specialized fibrous connective tissue and TME of pancreatic tumor, targeting Th17 cells only, or cytokine IL-17, is challenging to play a role in the treatment of complex pancreatic diseases. The interactions among intestinal microorganisms, host immune cells, and various immune regulatory factors need to be more in-depth understood for developing more effective therapeutic drugs.

Disclosure of conflict of interest

None.