Interleukin-17 as an effector molecule of innate and acquired immunity against infections

Interleukin (IL)-17 is a proinflammatory cytokine which induces differentiation and migration of neutrophils through induction of cytokines and chemokines including granulocyte-colony stimulating factor and CXCL8/IL-8. IL-17-producing CD4(+) T cells (Th17) have pivotal role in pathogenesis of autoimmune diseases. IL-17 is also involved in protective immunity against various infections. IL-17 has important role in induction of neutrophil-mediated protective immune response against extracellular bacterial or fungal pathogens such as Klebsiella pneumoniae and Candida albicans. Importance of IL-17 in protection against intracellular pathogens including Mycobacterium has also been reported. Interestingly, not only CD4(+) T cells but atypical CD4(-)CD8(-) T cells expressing T cell receptor (TCR) gammadelta produce IL-17, and IL-17 producing cells participate in both innate and acquired immune response to infections. Furthermore, neutrophil induction may not be the only mechanism of IL-17-mediated protective immunity. IL-17 seems to participate in host defense through regulation of cell-mediated immunity or induction of antimicrobial peptides such as beta-defensins. In this review, we summarize recent progress on the role of IL-17 in immune response against infections, and discuss possible application of IL-17 in prevention and treatment of infectious diseases.     

The role of interleukin-17 in the Helicobacter pylori induced infection and immunity

Background: Helicobacter pylori infection is regarded as the major cause of various gastric diseases and induces the production of several cytokines including interleukin‐17 (IL‐17) recently recognized as an important player in the mammalian immune system. Objective: This review deals with the role of IL‐17 on the H. pylori‐induced infection and immunity in humans and experimental animals. Results: H. pylori infection increases IL‐17 in the gastric mucosa of humans and experimental animals. In humans, IL‐17 induces the secretion of IL‐8 by activating the ERK 1/2 MAP kinase pathway and the released IL‐8 attracts neutrophils promoting inflammation. IL‐23 is increased in patients with H. pylori‐related gastritis and regulates IL‐17 secretion via STAT3 pathway. Studies in H. pylori‐infected mice indicate that IL‐17 is primarily associated with gastric inflammation. The early events in the immune response of immunized and challenged mice include the recruitment of T cells and the production of IL‐17. Neutrophil attracting chemokines are released, and the bacterial load is considerably reduced. IL‐17 plays a dual role in infection and vaccination. In infection, T regulatory cells (Tregs) suppress the inflammatory reaction driven by IL‐17 thereby favoring bacterial persistence. Immunization produces Helicobacter‐specific memory T‐helper cells that can possibly alter the ratio between T‐helper 17 and Treg responses so that the IL‐17‐driven inflammatory reaction can overcome the Treg response leading to bacterial clearance. Conclusion: IL‐17 plays an important role in H. pylori‐related gastritis and in the reduction of Helicobacter infection in mice following immunization.     

Signaling of interleukin-17 family cytokines in immunity and inflammation

IL-17 cytokine family, though still young since discovery, has recently emerged as critical players in immunity and inflammatory diseases. The prototype cytokine, IL-17A, plays essential roles in promoting inflammation and host defense. IL-17RA, a member of the IL-17 receptor family, forms a complex with another member, IL-17RC, to mediate effective signaling for IL-17A as well as IL-17F, which is most similar to IL-17A, via Act1 and TRAF6 factors. On the other hand, IL-17RA appears to interact with IL-17RB to regulate signaling by another cytokine IL-25. IL-25, the most distant from IL-17A in the IL-17 family, is involved in allergic disease and defense against helminthic parasites. In this review, we discuss recent advancements on signaling mechanisms and biological functions of IL-17A, IL-17F and IL-25, which will shed light on the remaining IL-17 family cytokines and help understand and treat inflammatory diseases.     

Interleukin‐17A‐producing T lymphocytes in chronic active Epstein–Barr virus infection

T helper (Th) 17 cells are reportedly effector T cells that produce interleukin (IL)‐17A and play a significant role in the development of autoimmune diseases and immune responses for antimicrobial host defense. Production of IL‐17A in chronic active Epstein–Barr virus infection (CAEBV) was studied to investigate its contribution to pathogenesis of this disease. Significantly more IL‐17A‐producing cells were detected in the peripheral blood of CAEBV patients than in that of healthy controls, although a significant difference in serum IL‐17A production was not confirmed. Of the IL‐17A‐producing cells, 91.8% were cluster of differentiation (CD)4‐positive Th17 cells. Moreover, there were significantly more IL‐17A‐producing cells among CD4⁺ cells in peripheral blood of CAEBV patients than in that of controls (1.97 ± 0.69% vs. 1.09 ± 0.53%, P = 0.0073). These data suggest that IL‐17A‐producing cells may influence the pathophysiology of CAEBV.     

Role of interleukin‐15 in cardiovascular diseases

Interleukin (IL)‐15 is a recently identified cytokine, which belongs to the interleukin‐2(IL‐2) family, and plays an important role in innate and adaptive immunoreaction. Given the fact that the structure of IL‐15 is partially similar to IL‐2, they share some common biological effects, including immunoregulation. IL‐2 was proven to protect cardiac function in mouse myocardial infarction models. Cardiovascular diseases (CVDs) dominate the cause of mortality worldwide. Besides atherosclerosis, inflammation is also widely involved in the pathogenesis of many CVDs including hypertension, heart failure (HF) and aneurysm. IL‐15, as a pro‐inflammatory cytokine, is up‐regulated in some cardiovascular diseases, such as myocardial infarction and atherosclerosis. The current understanding of IL‐15, including its signal pathway and cellular function, was described. Furthermore, IL‐15 has a protective effect in myocardial infarction and myocarditis by decreasing cardiomyocyte death and improving heart function. The inhibited effect of IL‐15 in ductus arteriosus (DA) should be focused on. IL‐15 promoted atherogenesis. IL‐15 may be a good target in treatment of cardiovascular diabetology. Finally, future research direction of IL‐15 deserves attention. Since IL‐15 plays several roles in CVDs, understanding the role of the IL‐15/IL‐15R system may provide a scientific basis for the development of new approaches that use IL‐15 for the treatment of CVDs.     

Association of interleukin‐17 gene polymorphisms and susceptibility to brucellosis in Hamadan,western Iran

IL‐17is one of the most important inflammatory cytokines that stimulate immunity responses in humans infected with Brucella species, acting as a regulator that reduces release of γ‐IFN, thus increasing resistance to brucellosis. Gene polymorphisms in the regulatory regions of cytokine‐encoding genes affect the amountsof cytokines produced and play a fundamental role in infectious diseases. The aim of this study was to determine the association between IL‐17 gene polymorphisms and susceptibility to brucellosis. In this case‐control study, 86 patients with brucellosis and 86 healthy persons in Hamadan, western Iran, from September 2014 to September 2016, were included. IL‐17 genetic variants at positions rs4711998 A/G, rs8193036 C/T, rs3819024 A/G, rs2275913 A/G, rs3819025 A/G, rs8193038 A/G, rs3804513 A/T, rs1974226 A/G and rs3748067 A/G were analyzed by restriction fragment length polymorphism‐PCR. Serum IL‐17 titers were measured by sandwich ELISA. GG genotypes at positions rs4711998 and rs3748067 were present significantly more frequently in patients with brucellosis than in controls (P < 0.05). The AA genotype at positions rs4711998, rs2275913 and rs3748067 and GG genotype at position rs19744226 were present significantly more frequently in controls than in the patient group. These results suggest that the AA genotype at positions rs3748067, rs3819025 and rs4711998 and GG genotype at position rs3819024 are likely protective factors against brucellosis, whereas the GG genotype at positions rs3748067, rs3819025 and rs4711998 and AA genotype at position rs3819024 may be risk factors against the disease. No significant relationships were found between serum IL‐17 titers and genotypes of the single‐nucleotide polymorphisms.     

Large numbers of interleukins‐22‐ and ‐17A‐producing T helper cells in cholangiocarcinoma related to liver fluke infection

Cholangiocarcinoma (CCA) associated with liver fluke infection involves inflammatory and immune processes; however, whether these involve the proinflammatory cytokine IL‐17A and proliferative cytokine IL‐22 remains unclear. Here, numbers of IL‐22‐ and IL‐17A‐producing Th cells and cytokine concentrations in 30 patients with CCA and long‐term liver fluke infection, 40 patients with liver‐fluke infection but not CCA, and 16 healthy controls were compared. Analyses were performed using immunohistochemistry, flow cytometry, ELISA and RT‐PCR. Immunohistochemical staining showed weaker expression of IL‐22 and IL‐17A in patients with CCA with than in those without liver fluke infection (P < 0.01). Flow cytometry revealed significantly greater median proportions of IL‐22‐producing T helper cells in patients with CCA (2.2%) than in those without it (0.69%) or controls (0.4%, P < 0.001). Similar results were obtained for IL‐17A‐producing T helper cells. ELISA revealed plasma concentrations of IL‐22 were 1.3‐fold higher in patients with CCA than in those without it and 4.6‐fold higher than in controls (P < 0.001). Plasma concentrations of IL‐17A were 2.5‐fold higher in patients with CCA than in those without it, and 21‐fold higher than in controls (P < 0.001). Amounts of IL‐22 and IL‐17A mRNAs in blood were significantly higher in patients with CCA than in the other two groups. Proportions of CD4⁺CD45RO⁺ T cells producing IL‐22 correlated with proportions producing IL‐17A (r = 0.759; P < 0.001), and plasma concentrations of IL‐22 correlated with those of IL‐17A (r = 0.726; P < 0.001). These results suggest that both IL‐17A and IL‐22 affect development of CCA related to liver fluke infection.

     

Analysis of oral microbial community and Th17‐associated cytokines in saliva of patients with oral lichen planus

Oral lichen planus (OLP) is a chronic inflammatory disorder of oral mucosa of unknown cause. Microbial infection and dysimmunity appear to play important roles in its pathogenesis. In this study, differences in genetic profiling of salivary microbial communities in two subtypes of OLP and healthy controls were evaluated by means of PCR‐denaturing gradient gel electrophoresis (DGGE). Additionally, ELISA was used to investigate the possible role of Th17 in lesion formation by detecting two related cytokines IL‐17 and IL‐23 in the saliva of OLP patients. When the DGGE profiles were analyzed, the bacterial populations were found to be significantly less rich in subjects with reticular and erosive OLP than in healthy controls. There was significantly less microbial diversity, as denoted by the Shannon index, in saliva samples from subjects with erosive OLP than in those from healthy controls. Cluster analysis and principal component analysis showed that the DGGE profiles formed distinctly group‐specific clusters. Salivary concentrations of IL‐17 in subjects with erosive OLP group were significantly higher than in those with reticular OLP and healthy controls. What's more, significantly positive correlations were observed between salivary IL‐17 concentrations and disease clinical scores. Microbial richness and diversity was negatively correlated with salivary IL‐17 concentrations. These results suggest there is significantly less salivary bacterial diversity and complexity in subjects with OLP han in healthy controls and that the shifted community composition is closely related to an immune cytokine, IL‐17.     

Identification of interleukin‐16 (IL‐16) and interleukin‐17D (IL‐17D) genes from Dabry's sturgeon (Acipenser dabryanus)

Dabry's sturgeon (Acipenser dabryanus) represents an ancient Actinopterygian lineage that are termed “living fossils”. Many diseases have been found in Dabry's sturgeon. In the present study, genes encoding interleukin (IL)‐16 and IL‐17D in Dabry's sturgeon were identified by RNA‐sequencing. Phylogenetic tree analysis suggested that they clustered together with the corresponding pro‐IL‐16 proteins and IL‐17D proteins from other fish. Sequence analysis revealed that IL‐17D protein was more conserved than pro‐IL‐16. Dabry's sturgeon pro‐IL‐16 contains four putative PDZ domains and do not include signal peptides, while IL‐17D only possesses signal peptides (1–25 aa). The expression patterns of IL‐16 and IL‐17D genes were investigated in Dabry's sturgeon to reveal their functions in disease. The expression level of IL‐16 showed no significant changes in embryos; however, the high expression level of IL‐17D at 0–14 hpf (hours post fertilization) implied the existence of maternal expression in the oocyte and an association with embryonic development. Tissue distribution analysis revealed that IL‐16 and IL‐17D proteins have potential functions in immune and non‐immune tissue compartments. IL‐16 and IL‐17D had different fold changes in primary spleen leukocytes after polyinosinic:polycytidylic acid (poly I:C) and lipopolysaccharide (LPS) administration, which suggested that IL‐16 has a stronger antiviral capability compared with its antibacterial response, and IL‐17D has a stronger antibacterial capability compared with its antiviral response. IL‐16 showed an earlier response to virus compared with IL‐17D, and IL‐17D showed earlier and shorter response to bacteria compared with IL‐16. Our findings suggested the roles of IL‐16 and IL‐17D in Dabry's sturgeon, and provided the theoretical basis for the prevention and control of diseases of Dabry's sturgeon.     

Fibroblast growth factor‐2 and interleukin‐4 synergistically induce eotaxin‐1 expression in adipose tissue‐derived stromal cells

The relationships between eosinophils and adipose tissues are involved in metabolic homeostasis. Eotaxin is a chemokine with potent effects on eosinophil migration. To clarify the mechanisms of eotaxin expression in adipose tissues, we examined the effects of fibroblast growth factor‐2 (FGF‐2) and interleukin‐4 (IL‐4) stimulation on eotaxin expression in adipose tissue‐derived stromal cells (ASCs), a type of adipocyte progenitor, in vitro. ASCs expressed eotaxin‐1 and did not express eotaxin‐2 or ‐3. Eotaxin‐1 expression was increased in a concentration‐dependent manner following FGF‐2 treatment. Additionally, ASCs expressed FGF receptor‐1 (FGFR‐1) and did not express FGFR‐2, ‐3, or ‐4. Eotaxin‐1 expression was inhibited in cells treated with the FGFR tyrosine kinase inhibitor and extracellular signal‐regulated kinase (ERK) inhibitor U0126, even in the presence of FGF‐2. Moreover, eotaxin‐1 expression was synergistically enhanced by combined treatment with FGF‐2 and IL‐4 and inhibited in the presence of U0126. Eotaxin‐1 expression induced by FGF‐2 and IL‐4 was involved in ERK activation via FGFR‐1 in ASCs. Upregulation of eotaxin expression in adipose tissues could increase eosinophil migration, thereby inducing IL‐4 secretion and activation of alternative macrophages and improving glucose homeostasis. These findings provide insights into the mechanisms through which eotaxin mediates metabolic homeostasis in adipose tissues and eosinophils.     

S100A9 gene silencing inhibits the release of pro‐inflammatory cytokines by blocking the IL‐17 signalling pathway in mice with acute pancreatitis

The study aimed to investigate whether S100A9 gene silencing mediating the IL‐17 pathway affected the release of pro‐inflammatory cytokines in acute pancreatitis (AP). Kunming mice were assigned to the normal, AP, AP + negative control (NC), AP + shRNA, AP + IgG and AP + anti IL‐17 groups. ELISA was applied to measure expressions of AMY, LDH, CRP, TNF‐α, IL‐6 and IL‐8. The cells were distributed into the control, blank, NC, shRNA1 and shRNA2 groups. MTT assay, flow cytometry, RT‐qPCR and Western blotting were used to evaluate cell proliferation, cell cycle and apoptosis, and expressions of S100A9, TLR4, RAGE, IL‐17, HMGB1 and S100A12 in tissues and cells. Compared with the normal group, the AP group displayed increased expressions of AMY, LDH, CRP, TNFα, IL‐6, IL‐8, S100A9, TLR4, RAGE, IL‐17, HMGB1 and S100A12. The AP + shRNA and AP + anti IL‐17 groups exhibited an opposite trend. The in vivo results: Compare with the control group, the blank, NC, shRNA1 and shRNA2 groups demonstrated increased expressions of S100A9, TLR4, RAGE, IL‐17, HMGB1 and S100A12, as well as cell apoptosis and cells at the G1 phase, with reduced proliferation. Compared with the blank and NC groups, the shRNA1 and shRNA2 groups had declined expressions of S100A9, TLR4, RAGE, IL‐17, HMGB1 and S100A12, as well as cell apoptosis and cells at the G1 phase, with elevated proliferation. The results indicated that S100A9 gene silencing suppressed the release of pro‐inflammatory cytokines through blocking of the IL‐17 pathway in AP.     

Clinical significance of weak interleukin‐35 expression in patients with psoriasis

CD4+T cells and their related cytokines play an important role in the pathogenesis of psoriasis, a chronic, recurrent, inflammatory skin disease. The role of IL‐35, an immunosuppressive cytokine involved in many autoimmune diseases, in the pathogenesis of psoriasis is unclear. In this study IL‐35 expression and its clinical significance in patients with psoriasis were evaluated. Protein and mRNA levels of specified markers were measured by ELISA and qRT‐PCR, respectively. It was found that plasma IL‐35 concentrations were lower in patients with psoriasis than in healthy individuals (Z = ?6.525, P < 0.0001). mRNA titers of Ebi3 and p35 were lower in peripheral blood mononuclear cells from patients with psoriasis than in those from healthy individuals (Z = ?5.078, P < 0.0001; Z = ?2.609, P = 0.009, respectively). The areas under the receiver‐operating characteristic (ROC) curves for IL‐35, Ebi3 and p35 in patients with psoriasis versus controls were 0.86, 0.78 and 0.64, respectively. Pearson correlation analysis showed that, in patients with psoriasis, plasma IL‐35 expression correlated negatively with concentrations of INF‐γ, tumor necrosis factor‐alpha, IL‐23, ?17, and ?22, and the Psoriasis Activity and Severity Index and positively with concentrations of transforming growth factor beta and IL‐10 . In summary, IL‐35 may mediate pathogenesis of psoriasis by influencing expression of Th1/Th17/T_reg‐related cytokines and may therefore be a putative target for monitoring or treating psoriasis.