Animals ; Antibodies, Monoclonal ; immunology ; Humans ; Receptors, Interleukin-17 ; immunology

CD4⁺Foxp3⁺ regulatory T (Treg) cells play major roles in immune homeostasis. While CD4⁺Foxp3⁺ Treg cells act to suppress other immune effector cells, there is growing evidence that they also produce pro-inflammatory cytokines, such as IL-17A, in inflammatory conditions. The pro-inflammatory cytokine milieu, toll-like receptor (TLR) signaling, and specific transcription factors are important for the production of IL-17A by CD4⁺Foxp3⁺ Treg cells. In particular, IL-17A-producing CD4⁺Foxp3⁺ Treg cells express RORγt, the T helper (Th) 17-specific transcription factor, in addition to Foxp3. IL-17A-producing CD4⁺Foxp3⁺ Treg cells are also involved in the pathogenesis of various diseases. Here we review the mechanisms underlying the induction of IL-17A-producing CD4⁺Foxp3⁺ Treg cells and the roles of these cells in human disease.
Cytokines ; Homeostasis ; Humans* ; Inflammation ; Interleukin-17 ; T-Lymphocytes, Regulatory* ; Toll-Like Receptors ; Transcription Factors

PURPOSE: Interleukin-17 (IL-17) is produced by activated CD4+T cells and exhibits pleiotropic biological activity on various cell types. IL-17 was reported to be involved in the immunoregulatory response in IgA nephropathy (IgAN). Our aim was to investigate the association between single-nucleotide polymorphisms (SNPs) in IL-17 receptor A (IL-17RA) gene and childhood IgAN. METHODS: We analyzed the SNPs in the IL-17RA in 156 children with biopsy-proven IgAN and 245 healthy controls. We divided the IgAN patients into 2 groups and compared them with respect to proteinuria (< or =4 and >4 mg/m2/h, < or =40 and >40 mg/m2/h, respectively) and the presence of pathological levels of biomarkers of diseases such as interstitial fibrosis, tubular atrophy, or global sclerosis. RESULTS: No difference was observed between the SNP genotypes rs2895332, rs1468488, and rs4819553 between IgAN patients and control subjects. In addition, no significant difference was observed between allele frequency of SNPs rs2895 332, rs1468488, and rs4819553 between patients in the early and advanced stage of the disease. However, significant difference was observed between the genotype of SNP rs2895332 between patients with proteinuria (>4 mg/m2/h) and those without proteinuria (codominant model OR 0.36, 95% CI 0.19-0.66, P<0.001; dominant model OR 0.35, 95% CI 0.17-0.69 P=0.002; recessive model OR 0.12, 95% CI 0.01-1.06 P=0.025). CONCLUSION: Our results indicate that the SNP in IL-17RA (rs2895332) may be related to the development of proteinuria in IgAN patients.
Atrophy ; Biomarkers ; Child ; Fibrosis ; Gene Frequency ; Genotype ; Glomerulonephritis ; Glomerulonephritis, IGA ; Humans ; Immunoglobulin A ; Interleukin-17 ; Polymorphism, Single Nucleotide ; Proteinuria ; Receptors, Interleukin-17

OBJECTIVETo detect the expression and distribution of interleukin-17 and interleukin 17 receptor (IL-17R) in nasal polyps and to probe into their significance in the pathology of nasal polyps.

METHODSThe methods of immunohistochemical staining and western blot were used to detect IL-17 and IL-17R in nasal polyps and controls.

RESULTSIn nasal polyp tissues, IL-17 expressed mainly in cytoplasm of plasm cell, less in prickle-cell layer of the epithelium and the acinus of the serous gland. In turbinates, IL-17 also expressed in the cytoplasm of the plasm cell, the prickle-cell layer of the epithelium and the acinus of the serous gland. The expression of IL-17 between nasal polyps and turbinates differed significantly (t = 2.237, 2.176, 2.246, P < 0.05, respectively). Both IL-17 and IL-17R displayed specific bands in nasal polyps and turbinates, but the bands of IL-17 and IL-17R in nasal polyps were stronger than those in turbinates.

CONCLUSIONSIL-17 may have an important role in the occurrence of nasal polyps by specific combination with IL-17R and over-expression in nasal polyps.

Adult ; Aged ; Case-Control Studies ; Female ; Humans ; Interleukin-17 ; metabolism ; Male ; Middle Aged ; Nasal Polyps ; metabolism ; pathology ; Receptors, Interleukin-17 ; metabolism

OBJECTIVE: To identify a gene expression signature in axial spondyloarthritis/ankylosing spondylitis (SpA/AS) and genomic pathways likely to be involved in pathogenesis of SpA/AS patients. METHODS: Four publicly accessible microarray studies from SpA/AS patients were integrated, and a transcriptomic and network-based meta-analysis was performed. This meta-analysis was compared with a published microarray study in whole blood of AS patients. RESULTS: According to our meta-analysis, 1,798 genes were differentially expressed in the whole blood of SpA/AS patients compared to healthy controls, while 674 genes were differentially expressed in the synovium of SpA/AS patients compared to healthy controls. When the whole blood meta-analysis data was compared with a published microarray study that also analyzed whole blood in SpA/AS patients, pathways involved in Toll-like receptor signaling, osteoclast differentiation, T cell receptor signaling and janus kinase–signal transducer and activator of transcription (Jak-STAT) signaling were often enriched in SpA/AS. On the other hand, eomesodermin, RUNX3, and interleukin-7 receptor (IL7R) were usually decreased in SpA/AS patients, suggesting that deficiency of these genes contributes to increased IL-17 production in AS. CONCLUSION: Several common enrichment pathways including Toll-like receptor signaling pathway, osteoclast differentiation, T cell receptor signaling pathway and Jak-STAT signaling pathway were identified in the differentially expressed genes of whole blood and synovium from SpA/AS patients, suggesting that these pathways are involved in the pathogenesis of SpA/AS.
Dataset* ; Gene Expression* ; Genes, vif ; Hand ; Humans ; Interleukin-17 ; Interleukin-7 ; Osteoclasts ; Receptors, Antigen, T-Cell ; Spondylitis ; Spondylitis, Ankylosing ; Synovial Membrane ; Toll-Like Receptors ; Transcriptome* ; Transducers

OBJECTIVE: To evaluate the expression of Toll-like receptor (TLR) 2, 4 and 9 and investigate the effects of IL-17 on the expression of TLRs in experimental rheumatoid arthritis (RA) model. METHODS: After induction of collagen-induced arthritis (CIA) by type II collagen in DBA1 mice, phosphate-buffered saline (PBS, PBS group) or IL-17 (IL-17 group) was injected to both knee joint at day 28 and 32. At day 35, mice were sacrificed and knee joints were isolated. Synovial mRNA expressions of TLR-2, 4 and 9 determined by real-time RT-PCR were compared among normal DBA1 mice (normal group), PBS and IL-17 group. RESULTS: Synovial TLR-2, 4, and 9 mRNA expressions of IL-17 and PBS group were significantly higher than normal group, and those of IL-17 group were higher than PBS group. CONCLUSION: Synovial TLR-2, 4 and 9 expression was enhanced in CIA and up-regulated by local overexpression of IL-17. These results suggest that TLRs play a roles on CIA and IL-17 induced aggravation of arthritis in CIA.
Animals ; Arthritis ; Arthritis, Experimental* ; Arthritis, Rheumatoid ; Collagen Type II ; Interleukin-17 ; Knee Joint ; Mice ; RNA, Messenger ; Toll-Like Receptors*

OBJECTIVE: The aim of this study was to clarify whether stimulation of recombinant IL-17, TLR2 and TLR4 by their specific ligands induces the production of RANKL and IL-6 in the fibroblast-like synoviocytes (FLSs) from RA patients. METHODS: FLSs were isolated from RA synovial tissues and they were stimulated with the IL-17, TLR2 ligand bacterial peptidoglycan (PGN) and TLR4 ligand lipopolysaccharide (LPS). The RANKL levels were assessed by RT-PCR and western blotting. The expressions of IL-17, TLR2, TLR4, RANKL and IL-6 in the RA synovium were quantified by immunohistochemistry and these values were compared with the values obtained in the osteoarthritis synovium. The increased IL-6 production in the culture supernatants of the RA FLSs was quantified by sandwich ELISA. RESULTS: The mRNA and protein levels of RANKL and IL-6 increased in the RA FLSs stimulated with PGN, LPS and IL-17, or PGN plus IL-17 or LPS plus IL-17. The expressions of IL-17, TLR2, TLR4, RANKL and IL-6 were much higher in the RA synovium than those in the osteoarthritis (OA) synovium. CONCLUSION: We observed synergistic effects of TLR-2, TLR-4 and IL-17 upon the induction of RANKL. In conclusion, our data supports the previous evidence of an important role of TLR-2, TLR-4 and IL-17 in the pathogenesis of RA.
Blotting, Western ; Fibroblasts ; Humans ; Immunohistochemistry ; Interleukin-17 ; Interleukin-6 ; Ligands ; Osteoarthritis ; Peptidoglycan ; RNA, Messenger ; Synovial Membrane ; Toll-Like Receptor 2 ; Toll-Like Receptor 4 ; Toll-Like Receptors

The recently identified interleukin-17 (IL-17) cytokines family, which comprises six members in mammals (IL-17A-F), plays essential roles in the host immunity against infectious diseases and chronic inflammatory diseases. The three-dimensional structures containing IL-17A or IL-17F have become available and revealed the unique structural features of IL-17s as well as their receptors. Molecular modeling in this review shows that IL-17s may adopt a "cysteine knot" fold commonly seen in nerve growth factor (NGF) and other neurotrophins. Further modeling analysis unmasks a signature interaction feature of the IL-17F/IL-17RA complex, where a small loop of IL-17RA slots into the deep groove of the interface of IL-17F homodimer. This is quite different from the interaction between the best known four-helix cytokines and their cognate receptors. On the other hand, structure of IL-17A and its monoclonal antibody (CAT-2200) shows that, albeit that the antigenic epitope of IL-17A resides outside of the IL-17A homodimer interface, its physical proximity to the receptor binding groove may explain that antibody blockage would be achieved by interfering with the ligand-receptor interaction. This review is to summarize the advance in understanding the structure and function of IL-17 family cytokines, focusing mainly on IL-17A, IL-17F and IL-17E, in the hope of gaining better knowledge of immunotherapeutic strategies against various inflammatory diseases.
Amino Acid Sequence ; Animals ; Conserved Sequence ; Cysteine ; Disulfides ; chemistry ; Humans ; Interleukin-17 ; chemistry ; metabolism ; Molecular Sequence Data ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptors, Interleukin ; metabolism

ATP-Binding Cassette Transporters ; genetics ; DNA Copy Number Variations ; genetics ; Genetic Predisposition to Disease ; Gout ; genetics ; Humans ; Receptors, IgG ; genetics ; Receptors, Interleukin-17 ; genetics

The purpose of this study was to determine the expression levels of IL-17 in serum and IL-17 receptor (IL-17R) in intestinal mucosa tissue in patients with ulcerative colitis (UC) and controls, and evaluate their relationship with disease activity and explore the role of IL-17 in the patho-genesis of UC. A total of 36 Chinese UC patients and 60 healthy controls were enrolled in this study. Serum IL-17 and C-reactive protein (CRP) levels were determined by ELISA and immunonephelometry, respectively. The IL-17R mRNA expression levels were detected by quantitative PCR. Serum IL-17 levels were significantly elevated in UC patients as compared with those in the healthy controls (P<0.05). Among UC patients, serum IL-17 levels were significantly increased in active phase as compared with those in inactive phase (P<0.05), and correlated with CRP levels (r=0.578, P<0.01). IL-17R expression levels were higher in active UC patients than in healthy controls (P<0.05). It was concluded that IL-17 levels were highly expressed in UC, especially in active phase, and correlated with CRP levels in UC patients.
Adult ; Biomarkers ; blood ; C-Reactive Protein ; metabolism ; Case-Control Studies ; Colitis, Ulcerative ; blood ; pathology ; Female ; Humans ; Interleukin-17 ; blood ; Male ; Middle Aged ; RNA, Messenger ; blood ; Receptors, Interleukin-17 ; genetics ; metabolism