IL-27: a novel cytokine mediating immune related diseases / 生理学报

Interleukin 27 (IL-27) is a pleiotropic cytokine that is involved in the regulation of the body's innate and adaptive immunity. Previous studies have shown that IL-27 mediates a variety of inflammatory responses in vivo. With the development of animal models and technical tools, several studies have shown that it is also closely associated with autoimmune diseases and other immune related diseases, and is considered as an important candidate for the treatment of viral disease, autoimmune diseases, tumors and obesity. Therefore, this paper reviews recent progress on the role of IL-27 in acquired immunodeficiency syndrome (AIDS), rheumatoid arthritis, tumors and obesity, with the aim of providing new ideas for the treatment of immune related diseases.

A pilot study of plasma interleukin-6 and interleukin-27 in differential diagnosis of acute respiratory distress syndrome and neonatal respiratory distress syndrome in preterm infants / 中国当代儿科杂志

OBJECTIVES@#To study the significance of interleukin-6 (IL-6) and interleukin-27 (IL-27) in the differential diagnosis of acute respiratory distress syndrome (ARDS) and neonatal respiratory distress syndrome (NRDS) in preterm infants.@*METHODS@#The preterm infants with the manifestation of respiratory distress who were treated in the Neonatal Diagnosis and Treatment Center, Children's Hospital of Chongqing Medical University, from March to November 2021, were enrolled in this prospective study. According to the diagnosis results, they were divided into two groups: ARDS group (n=18) and NRDS group (n=20). ELISA was used to measure the plasma levels of IL-6 and IL-27. The receiver operating characteristic (ROC) curve was used to analyze the value of each index in the diagnosis of ARDS.@*RESULTS@#The ARDS group had significantly higher plasma levels of IL-6 and IL-27 than the NRDS group (P<0.05). The ROC curve analysis showed that IL-6 had an area under the ROC curve (AUC) of 0.867 for the diagnosis of ARDS, with a sensitivity of 61.1% and a specificity of 95.0% at the cut-off value of 56.21 pg/mL. The ROC curve analysis also showed that IL-27 had an AUC of 0.881 for the diagnosis of ARDS, with a sensitivity of 83.3% and a specificity of 80.0% at the cut-off value of 135.8 pg/mL.@*CONCLUSIONS@#Plasma IL-6 and IL-27 can be used as biological indicators for early differential diagnosis of ARDS and NRDS in preterm infants.

Decreased levels of interleukin 27 in the serum of vitiligo patients

Abstract Background: Vitiligo is a common skin disorder in which melanocytes are destroyed by auto-reactive immune responses. The loss of melanocytes results in the appearance of depigmented areas in different parts of the body. Cytokines have remarkable roles in the pathogenesis of vitiligo, such as IL-1, IL-6, and TNF-α; interleukin 27 (IL-27) is a new member of the IL-6/IL-12 family, mainly released by activated antigen-presenting cells. IL-27 has been suggested to function as a pro-inflammatory as well as an anti-inflammatory cytokine. Altered concentrations of IL-27 have been shown in various auto-immune diseases such as multiple sclerosis, rheumatoid arthritis, and psoriasis. No studies have been conducted to determine the expression of this cytokine in vitiligo patients. Objective: The objective of this study was to determine the serum concentration of IL-27 in vitiligo patients and compare it with normal individuals. Methods: The serum concentration of IL-27 in 79 vitiligo patients was evaluated in comparison to 45 healthy controls using ELISA assay. Results: Results showed decreased concentration of IL-27 in vitiligo patients as compared with healthy subjects (p = 0.026). Furthermore, no correlation between IL-27 concentrations and disease parameters such as vitiligo severity and the extension of the depigmented area was observed. Study limitation: A larger sample size would be more recommended for this study. Conclusion: The reduction in the serum levels of IL-27 in vitiligo patients compared to normal subjects suggested the possible anti-inflammatory role of this cytokine in vitiligo. Thus, IL-27 may be considered as a new target for the manipulation of the immune system in vitiligo patients.

Effects of IL-27 on Th17 Cells in Patients with Henoch-Schönlein Purpura / 中国实验血液学杂志

OBJECTIVE@#To investigate the effect of IL-27 on Th17 cells in patients with henoch-schönlein purpura（HSP） in order to further elucidate the pathogenesis.@*METHODS@#Fifty patients with HSP treated in our hospital from April 2019 to July 2019 were selected as HSP group, and 30 volunteers underwent physical examination at the same time were selected as control group. The proportion of Th17 cells in peripheral blood of HSP group and healthy control group was determined by flow cytometry (FCM). A total of 27 HSP patients were selected, and candidate peripheral blood mononuclear lymphocytes (PBMC) were co-cultured with exogenous rhIL-27, and the ratio of Th17 cells was detected by flow cytometry.@*RESULTS@#The proportion of Th17 cells in the peripheral blood of HSP patients with acute phase was (1.57±0.54)%, which was significantly higher than that of the control group (0.86±0.40)% (t=-6.298, P<0.001), and the proportion of Th17 cells was decreased significantly after rhIL-27 co-culture (1.39%±0.52% vs 0.98%±0.44%)(P<0.05).@*CONCLUSION@#IL-27 can reduce the level of Th17 cells in patients with HSP, which may be involved in the pathogenic process of HSP and play a protective role in the development of the disease.

Regulation of Osteoclast Differentiation by Cytokine Networks

Cytokines play a pivotal role in maintaining bone homeostasis. Osteoclasts (OCs), the sole bone resorbing cells, are regulated by numerous cytokines. Macrophage colony-stimulating factor and receptor activator of NF-κB ligand play a central role in OC differentiation, which is also termed osteoclastogenesis. Osteoclastogenic cytokines, including tumor necrosis factor-α, IL-1, IL-6, IL-7, IL-8, IL-11, IL-15, IL-17, IL-23, and IL-34, promote OC differentiation, whereas anti-osteoclastogenic cytokines, including interferon (IFN)-α, IFN-β, IFN-γ, IL-3, IL-4, IL-10, IL-12, IL-27, and IL-33, downregulate OC differentiation. Therefore, dynamic regulation of osteoclastogenic and anti-osteoclastogenic cytokines is important in maintaining the balance between bone-resorbing OCs and bone-forming osteoblasts (OBs), which eventually affects bone integrity. This review outlines the osteoclastogenic and anti-osteoclastogenic properties of cytokines with regard to osteoimmunology, and summarizes our current understanding of the roles these cytokines play in osteoclastogenesis.

Serum Cytokine Profile in Patients with Chronic Rhinosinusitis with Nasal Polyposis Infected by Aspergillus flavus

BACKGROUND: Fungi, especially Aspergillus flavus, can cause chronic rhinosinusitis with nasal polyposis and modulate host innate immune components. The objective of this study was to examine the serum levels of T helper (Th) cell subset Th1, Th2, and Th17 cytokines and total IgE in patients having chronic rhinosinusitis with nasal polyposis and Aspergillus flavus infection. METHODS: A case-control study including 40 patients with chronic rhinosinusitis with nasal polyposis and 20 healthy controls was conducted. Aspergillus flavus infection was confirmed by standard potassium hydroxide (KOH) testing, culture, and PCR. Serum samples of all patients and controls were analyzed for various cytokines (interleukins [IL]-1β, IL-2, IL-4, IL-6, IL-17, IL-21, IL-27, TGF-β) and total IgE by ELISA. Data from patients with Aspergillus flavus infection and healthy volunteers were compared using the independent t-test and non-parametric Mann-Whitney U test. RESULTS: Aspergillus flavus infection was found in 31 (77.5%) patients with chronic rhinosinusitis with nasal polyposis. IL-1β, IL-17, IL-21, and TGF-β serum levels were significantly higher in these patients than in controls; however, IL-2, IL-4, IL-6, and IL-27 levels were lower. Compared with nine (22.5%) patients without Aspergillus flavus infection, IL-17 level was higher while IL-2 level was lower in patients with Aspergillus flavus infection. Total IgE was significantly higher in patients with Aspergillus flavus infection than in controls. CONCLUSIONS: High levels of IL-17 and its regulatory cytokines in patients with chronic rhinosinusitis with nasal polyposis infected by Aspergillus flavus raise a concern about effective disease management and therapeutic recovery. Surgical removal of the nasal polyp being the chief management option, the choice of post-operative drugs may differ in eosinophilic vs. non-eosinophilic nasal polyposis. The prognosis is likely poor, warranting extended care.

Interleukin-27 augments the inhibitory effects of sorafenib on bladder cancer cells

Both sorafenib and interleukin-27 (IL-27) are antineoplastic drugs. This study aimed to investigate the synergistic effect of these two drugs on bladder cancer cells. HTB-9 and T24 cells were stimulated with IL-27 (50 ng/mL), sorafenib (2 μM) or the synergistic action of these two drugs. The cells without treatment acted as control. Cell proliferation, apoptosis and invasion were measured by bromodeoxyuridine assay, flow cytometry and modified Boyden chamber, respectively. Simultaneously, both modified Boyden chamber and scratch assay were used to assess cell migration. Finally, the phosphorylation levels of key kinases in the Akt/mechanistic target of rapamycin (mTOR)/mitogen-activated protein kinase (MAPK) pathway, and expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 were detected by western blot analysis. Stimulation with IL-27 or sorafenib repressed proliferation, migration and invasion but promoted apoptosis, and the effects were all enhanced by the combination of these two drugs in HTB-9 cells. The effect of the combined treatment on bladder cancer cells was verified in T24 cells. Additionally, the phosphorylation levels of AKT, mTOR and MAPK as well as the expression levels of MMP-2 and MMP-9 were all decreased by a single treatment of IL-27 or sorafenib, and further decreased by the combined treatment of these two drugs. The combination of IL-27 and sorafenib inhibited proliferation, migration and invasion and promoted apoptosis of bladder cancer cells compared with mono-drug treatment. Additionally, the AKT/mTOR/MAPK pathway might be implicated in the functional effects by down-regulations of MMP-2 and MMP-9.

Expression of interleukin-12 and interleukin-27 proteins and immune status in serum of patients with oral lichen planus / 华西口腔医学杂志

<p><b>OBJECTIVE</b>This study aimed to conduct a preliminary study on the possible role and significance of interleukin (IL)-12 and IL-27 in the pathogeneses of oral lichen planus (OLP).</p><p><b>METHODS</b>Thirty cases of patients with OLP (fifteen cases of reticular OLP and fifteen cases of erosive OLP) were enrolled in this study, and twenty cases of healthy people served as controls. Lymphocyte subsets CD3+, CD4+, CD8+, CD19+, and CD16+56 [natural killer cell (NK)] were tested using flow cytometry, and humoral immunity [immunoglobulin (Ig)G, IgA, IgM, C3, C4] were examined using nephelometry assays. IL-12 and IL-27 contents in serum of patients with OLP and normal controls were detected through enzyme linked immunosorbent assay. The correlations between the levels of IL-12, IL-27, immune status, and clinical characteristics of patients with OLP were analyzed, respectively.</p><p><b>RESULTS</b>CD3+, CD4+, and CD8+in patients with OLP were markedly lower than the normal value, whereas CD 19+ of OLP in patients was significantly higher than the normal value (P<0.05). IgM inpatients with OLP was increased, whereas C4 was declined (P<0.05). IL-12 and IL-27 levels showed significant upregulation or ULF patients compared with control groups (P<0.05). Meanwhile, positive correlations existed between IL-12 andIL-27 levels in the serum of patients with OLP (r=0.912, P<0.01). No significant correlations of IL-12 and IL-27 epressions with clinical characteristics of OLP were found (P>0.05). Negative correlations of IL-12 and IL-27 levels with CD16+56(NK) cells were observed (r1 = -0.416, P1 = 0.022; r2 = -0.392, P2=0.032, respectively), whereas a positive correlation existed for IgG (r1=0.445, P1=0.014; n=0.549, P2=0.002, respectively).</p><p><b>CONCLUSION</b>A cellular immune dysfunction mainly dominate in patients with OLP, accompanied by some degree of humoral-immunity-function disorder. The abnormally high expressions of IL-12 and IL-27 are possibly synergized and promoted inflammation development in OLP. Its promotion takes place through the negatie feedback regulation of humoral immune responses, which are involved in the regulation of immune mechanisms of OLP.</p>

association between single nucleotide polymorphism in interleukin-27 gene and recurrent pregnancy loss in Iranian women

Recurrent pregnancy loss [RPL] has been defined as two or more miscarriages before 20[th] week of gestation. It seems that IL-27 may reduce inflammatory responses and affect the survival of the embryo during human pregnancy. IL-27 polymorphisms may influence RPL by altering the levels or the activity of gene product. We studied for the first time the association of IL-27 -964 A>G single nucleotide polymorphism [SNP] with RPL in Iranian women. A case-controlled study was performed on two groups consisting of 150 healthy women with at least one delivery [control group] and 150 women with two or more primary RPLs history [RPL group]. The -964 A>G SNP in IL-27 gene was determined by PCR-RFLP technique. Genotype and allele frequencies were compared using Chi[2] tests between two groups. There was no difference between the two groups regarding age of women [29 +/- 4.4 [control] vs. 30.84 +/- 5.2 years [case]]. In the RPL group, the genotype frequencies of -964 A>G polymorphism were AG [49.3%], AA [40%], and GG [10.7%], and in the control group, they were AG [43.3%], AA [48.7%], and GG [8%]. There was no significant difference between the genotypes of AA, AG, and GG in two groups [p=0.23]. As the frequency of allele A was 64.7% in the RPL group and 70.3% in the control group, the difference in frequency of allele A in -964 A>G between two groups was not significant [p=0.19]. Our findings indicate that SNP of -964 A>G in IL-27 gene is not a risk factor for RPL in Iranian women

Progress on interleukin-27 in tumor immunity / 浙江大学学报·医学版

As a member of IL-6/IL-12 cytokine family, IL-27 is a heterodimeric cytokine composed of the p28 and EBI3. Functioning as a linkage between innate and adaptive immunity, IL-27 is mainly produced by activated antigen-presenting cells and has a variety of responder cells including T cells, NK cells, macrophages and dendritic cells. IL-27 plays an antitumor role through promoting the production of cytotoxic T cells, regulating the differentiation of T cell subsets, enhancing the function of NK cells and inhibiting the angiogenesis. On the other hand, IL-27 may also have a positive effect on tumor progress and metastasis. IL-27 can be used as a reference marker for tumor diagnosis, due to its relation to the occurrence and development of tumors. This article reviews the research progress on the roles of IL-27 in tumor biological regulation.

Interleukin-17 contributes to the macrophage secretion of interleukin-27 in a murine model of viral myocarditis / 中华心血管病杂志

<p><b>OBJECTIVE</b>Interleukin-27 (IL-27) has been reported to reduce the levels of interleukin-17 (IL-17) and alleviate the severity of experimental autoimmune myocarditis. IL-17, an important tissue-protective cytokine in viral myocarditis (VMC), has been reported to increase synovial expression of IL-27 in rheumatoid arthritis. However, the influence of IL-17 on IL-27 expression in murine model of VMC remains unknown.</p><p><b>METHODS</b>Wild-type (WT) and IL-17A-deficient (IL-17A(-/-)) mice on the BALB/c background were intraperitoneally (i.p) injected with coxsackievirus B3 (CVB3) for establishing VMC models. Cardiac tissue was obtained on day 7 after CVB3 injection. Myocardial histopathologic changes were observed by hematoxylin-eosin (HE) stained myocardial sections.Expression of IL-27 in heart and serum was measured by real-time reverse transcription-polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA), respectively. Furthermore, splenic lymphocytes and peritoneal macrophages were purified 1 week after injection from WT mice.Isolated lymphocytes were cultured in the presence of different concentrations (0 and 25 ng/ml) of recombinant IL-17 (rIL-17) for 24 h. Macrophages were cultured with different concentrations of rIL-17 (0 and 10 ng/ml) for 48 h.IL-27 mRNA expression of cultured cells was assayed by RT-PCR, and their protein level in the culture supernatant was measured by ELISA.</p><p><b>RESULTS</b>Compared with WT mice, significantly less cardiac inflammation was evidenced in the heart of IL-17A-/- mice (0.9 ± 0.3 vs.1.9 ± 0.5) , relative cardiac IL-27 p28 mRNA expressions (1.11 ± 0.24 vs.3.1 ± 0.8) and serum IL-27 protein[(72 ± 18) pg/ml vs.(95 ± 25) pg/ml] were also significantly lower in IL-17A-/- mice (all P < 0.05).In the culture lymphocytes, the relative mRNA (1.02 ± 0.13 vs.1.32 ± 0.21) and protein [(49 ± 9) pg/ml vs.(52 ± 11) pg/ml]expressions of IL-27 p28 and were similar post treatment with 0 and 25 ng/ml rIL-17 (all P > 0.05). Compared with 0 ng/ml rIL-17 culture with macrophages, higher relative mRNA (8.5 ± 3.1 vs.2.2 ± 0.7) and protein [(368 ± 95) pg/ml vs.(150 ± 38) pg/ml] expressions of IL-27 p28 were detected in 10 ng/ml rIL-17 group (all P < 0.05).</p><p><b>CONCLUSION</b>Our data indicates that cytokine IL-17 may contribute to the secretion of IL-27 in VMC mice.Furthermore, macrophages but not lymphocytes may be the important IL-27-producing immune cells and major target cells for IL-17. Thus,IL-27 and IL-17 might be actively involved in the pathogenesis of VMC.</p>

Association of Interleukin 27 gene polymorphism and risk of Hepatitis B viral infection in Egyptian population

According to the World Health Organization, Hepatitis B virus [HBV] is considered a major global public health problem. The genetic background may be a crucial etiologic factor in HBV infection and its complications. Interleukin-27 [IL-27] is a newly discovered cytokine encoded by 2 genes [EBI3 and p28]. Mutations in the IL-27 gene may lead to altered cytokine production and/or activity and thus modulate individual's susceptibility to HVB infection. This work was designed to study the association of IL-27p28 [964A/G, 2905T/G and 4730T/C] gene promoter single nucleotide polymorphism [SNP] with the risk of Hepatitis B virus [HBV] in Egyptians. To the best of our knowledge, this study is the first one that examines IL-27p28 promoter polymorphism in Egyptian patients. One hundred and sixteen patients with HBV infection and 101 healthy controls were genotyped by using polymerase chain reaction/restriction fragment length polymorphism [PCR/RFLP] in Egyptian population. There were no significant differences in the genotype and allele frequencies of IL-27p28 gene polymorphisms between patients and controls. Furthermore, no association was found between the distributions of the haplotypes and HBV risk. Our data suggested that polymorphisms in the IL-27 gene may not contribute to HBV susceptibility. Further studies with large sample size should be conducted to validate these results in Egyptian population

Lentiviral mediating genetic engineered mesenchymal stem cells for releasing IL-27 as a gene therapy approach for autoimmune diseases

Autoimmune diseases precede a complex dysregulation of the immune system. T helper17 [Th17] and interleukin [IL]-17 have central roles in initiation of inflammation and subsequent autoimmune diseases. IL-27 significantly controls autoimmune diseases by Th17 and IL-17 suppression. In the present study we have created genetic engineered mesenchymal stem cells [MSCs] that mediate with lentiviral vectors to release IL-27 as an adequate vehicle for ex vivo gene therapy in the reduction of inflammation and autoimmune diseases. In this experimental study, we isolated adipose-derived MSCs [AD-MSCs] from lipoaspirate and subsequently characterized them by differentiation. Two subunits of IL-27 [p28 and EBI3] were cloned in a pCDH-513B-1 lentiviral vector. Expressions of p28 and EBI3 [Epstein-Barr virus induced gene 3] were determined by real time polymerase chain reaction [PCR]. MSCs were transduced by a pCDH-CMV-p28-IRESEBI3- EF-copGFP-Pur lentiviral vector and the bioassay of IL-27 was evaluated by IL-10 expression. Cell differentiation confirmed true isolation of MSCs from lipoaspirate. Restriction enzyme digestion and sequencing verified successful cloning of both p28 and EBI3 in the pCDH-513B-1 lentiviral vector. Real time PCR showed high expressions level of IL-27 and IL-10 as well as accurate activity of IL-27. The results showed transduction of functional IL-27 to AD-MSCs by means of a lentiviral vector. The lentiviral vector did not impact MSC characteristics

Combined detections of interleukin 27, interferon-γ, and adenosine deaminase in pleural effusion for diagnosis of tuberculous pleurisy / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Previous studies reported interleukin-27 (IL-27), interferon-γ (IFN-γ), or adenosine deaminase (ADA) alone plays a helpful role in diagnosing tuberculous pleural effusion (TPE). The present study aims at comparing the diagnostic accuracy of pleural IL-27, IFN-γ, and ADA, and investigate the diagnostic accuracy of the combination of IL-27, IFN-γ, or/and ADA for differentiating TPE from pleural effusions with the other etiologies.</p><p><b>METHODS</b>The concentrations of IL-27, IFN-γ and ADA were simultaneously determined in pleural fluids and sera from 40 patients with TPE; 26 with malignant pleural effusion, seven with infectious pleural effusion, and eight with transudative pleural effusion by enzyme linked immunosorbent assay and colorimetric method. The corresponding biochemical indexs were also simultaneously determined.</p><p><b>RESULTS</b>The concentrations of pleural IL-27 and IFN-γ in the tuberculous group were significantly higher than those in the malignant, infectious, and transudative groups. The concentrations of ADA in TPE were significantly higher than those in MPE or transudative effusions, while much lower than those in infectious effusions. Among these three biomarkers, IL-27 was the most effective for TPE diagnosis, with the cut off value of 900.8 ng/L. IL-27 had a high sensitivity of 95% and specificity of 97.6% for differential diagnosis of TPE from non-TPEs. Combinations of IL-27, IFN-γ and ADA measurements further increased the sensitivity or specificity up to 100%.</p><p><b>CONCLUSIONS</b>Compared to non-TPEs, IL-27, IFN-γ and ADA all simultaneously increased in TPE; and among these three rapid detection methods, IL-27 appeared to be the best for distinguishing tuberculous from non-TPEs, especially from MPE. Combinations of the three markers (IL-27, IFN-γ and ADA) yielded the highest sensitivity and specificity. These findings suggest that the applications of a new biomarker, IL-27, alone or with IFN-γ and ADA, may contribute to more efficient diagnosis strategies in the management of tuberculous pleurisy.</p>

Increased IL-17A but decreased IL-27 serum levels in patients with multiple sclerosis

Effector CD4[+] T cell subsets play an important role in Multiple Sclerosis [MS]. Interleukin-27 [IL-27] suppresses Th [Th1, Th2 and Th17] cells and dampens autoimmunity and tissue inflammation by promoting the generation of Type 1 regulatory T cells [Tr1]. To identify the relative levels of IL-27 and IL-17A in MS disease. In a case-control study, venous blood was collected from forty MS patients and forty-three healthy subjects as control group. Serum levels of IL-27 and IL- 17A were measured by ELISA method. A significant difference between serum IL-17A concentration in patients [120.68 +/- 209.85 pg/ml] and control group [67.26 +/- 117.76 pg/ml, p=0.016] was found. Serum IL-27 levels of the MS patients [159.7 +/- 581.4 pg/ml] were significantly lower than control subjects [180.35 +/- 507.84 pg/ml, p=0.001]. Our findings show decreased levels of IL-27 against increasing IL-17A levels in patients group which may suggest the suppressive role of IL-27 on inflammatory process of MS