Fluoride induces apoptosis and autophagy through the IL-17 signaling pathway in mice hepatocytes.

Previous studies have reported that excessive fluoride exposure induced liver damage. However, the underlying mechanism of fluoride-induced hepatic toxicity is still unclear. Hence, this study was aimed to evaluate the fluoride-induced apoptosis, autophagy, and IL-17 signaling pathway-related genes to explore the possible mechanisms of NaF-induced liver injury in mice. For this, 48 male mice were allotted randomly to four groups, treated with deionized water, 25, 50, 100 mg/L NaF for 150 days continuously. Our results suggested that treatment with NaF decreased the PAS staining-positive area, with a concomitant increase in liver score, and serum ALT and AST levels which indicated that NaF induced the liver injury. In addition, the qRT-PCR, immunohistochemistry, and western blotting results indicated that NaF exposure activated IL-17 signaling, apoptosis, and autophagy pathways. In summary, these results suggested that NaF induced apoptosis and autophagy in liver by activating the IL-17 signaling pathway, eventually leading to impaired liver function.

Genetic determinants and postorthodontic external apical root resorption in Czech children.

OBJECTIVE: Genes, involved in the modulation of inflammatory response and bone remodeling, play a role in the development of postorthodontic external apical root resorption (EARR). The aim of our study was to analyze possible associations between seven single nucleotide polymorphisms (SNPs) in interleukin-17A (IL-17), osteopontin (SPP1), purinoreceptor P2X7 (P2RX7), and tumor necrosis factor receptor superfamily member 11B (TNFRSF11B) genes and EARR in children after orthodontic treatment. SUBJECTS AND METHODS: This case-control study comprised 99 orthodontically treated patients (69 controls and 30 subjects with EARR). Genotype determinations of rs2275913, rs11730582, rs9138, rs208294, rs1718119, rs3102735, and rs2073618 were based on polymerase chain reaction using 5' nuclease TaqMan® assays. RESULTS: While no significant differences were observed in allele or genotype frequencies of all seven studied SNPs, specific haplotype of P2RX7 (rs208294 and rs1718119) modified the risk of EARR development (P < 0.05). In addition, the length of treatment with a fixed orthodontic appliance positively correlated with the presence of EARR (P < 0.05). CONCLUSIONS: Although the effect of individual SNPs studied on the EARR development was not confirmed in the Czech population, complex analysis suggested that variability in the P2RX7 gene and the length of orthodontic treatment may be important factors contributing to the etiopathogenesis of postorthodontic EARR.

IL-17 receptor A signaling is protective in infection-stimulated periapical bone destruction.

IL-17 is a pleiotropic cytokine produced by Th17 T cells that induces a myriad of proinflammatory mediators. However, different models of inflammation report opposite functional roles of IL-17 signal in terms of its effects on bone destruction. In this study we determined the role of IL-17RA signal in bone resorption stimulated by dentoalveolar infections. Infrabony resorptive lesions were induced by surgical pulp exposure and microbial infection of mouse molar teeth. IL-17 was strongly induced in periapical tissues in wild-type (WT) mice by 7 d after the infection but was not expressed in uninfected mice. Dentoalveolar infections of IL-17RA knockout (KO) mice demonstrated significantly increased bone destruction and more abscess formation in the apical area compared with WT mice. Infected IL-17RA KO mice exhibited significantly increased neutrophils and macrophages compared with the WT littermates at day 21, suggesting a failure of transition from acute to chronic inflammation in the IL-17RA KO mice. The expression of IL-1 (both α and ß isoforms) and MIP2 were significantly upregulated in the IL-17RA KO compared with WT mice at day 21 postinfection. The development of periapical lesions in IL-17RA KO mice was significantly attenuated by neutralization of IL-1ß and MIP2. Taken together, these results demonstrate that IL-17RA signal seems to be protective against infection-induced periapical inflammation and bone destruction via suppression of neutrophil and mononuclear inflammation.

IL-17 stimulates the production of the inflammatory chemokines IL-6 and IL-8 in human dental pulp fibroblasts.

AIM: To investigate IL-17 expression in human pulpitis and to study the effects of IL-17 on the secretion of the chemokines IL-6 and IL-8 and the related signalling pathways. METHODOLOGY: Samples of human dental pulp tissue were obtained from healthy controls and patients with pulpitis. Cytokine IL-17 messenger RNA (mRNA) expression in the pulp tissue was detected by real-time polymerase chain reaction. In addition, human dental pulp fibroblasts (HDPFs) were stimulated with IL-17. Production of IL-6 and IL-8 was determined by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. Aspects of the nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) signalling pathways were examined by Western blot analysis. RESULT: Increased levels of IL-17 mRNA were found in inflamed dental pulp tissue (pulpitis). Stimulation of dental pulp tissue with IL-17 induced the production of IL-6 and IL-8 in a dose-dependent manner. In addition, IL-17 stimulation resulted in rapid activation of nuclear factor-kappaB (NF-κB), phosphorylation of p38 MAPK, extracellular signal-regulated kinase (ERK) and Jun N-terminal kinase (JNK) in HDPFs. CONCLUSION: IL-17 may participate in pulp tissue inflammation through chemokine production and NF-κB and MAPKs signalling pathways.

Salivary gland hypofunction induced by activation of innate immunity is dependent on type I interferon signaling.

BACKGROUND: Activation of innate immunity through polyinosinic:polycytidylic acid [poly(I:C)] causes acute salivary gland hypofunction. As a major consequence of poly(I:C) treatment is type I interferon (IFN) production, this study was undertaken to investigate their role in salivary gland dysfunction. METHODS: Different strains of mice deficient in either interferon alpha receptor (IFNAR1(-/-)) or IL-6(-/-), or IL-10(-/-), or EBI3(-/-) were treated with poly(I:C). Salivary gland function was determined by measuring pilocarpine-induced saliva volume. Gene expression levels were measured by real-time PCR. Ca(2+) mobilization studies were performed using ex-vivo acinar cells. RESULTS: A single injection of poly(I:C) rapidly induced salivary gland hypofunction in wild-type B6 mice (41% drop in saliva volumes compared to PBS-treated mice). In contrast, the loss of function in poly(I:C)-treated IFNAR(-/-) mice was only 9.6%. Gene expression analysis showed reduced levels of Il-6, Il-10, and Il-27 in submandibular glands of poly(I:C)-treated IFNAR(-/-) mice. While salivary gland dysfunction in poly(I:C)-treated IL-10(-/-) and EBI3(-/-) mice was comparable to wild-type mice, the IL-6(-/-) mice were more resistant, with only a 21% drop in function. Pilocarpine-induced Ca(2+) flux was significantly suppressed in acinar cells obtained from poly(I:C)-treated wild-type mice. CONCLUSIONS: Our data demonstrate that a combined action of type I IFNs and IL-6 contributes toward salivary gland hypofunction. This happens through interference with Ca(2+) mobilization within acinar cells. Thus, in acute viral infections and diseases like Sjögren's syndrome, elevated levels of type I IFNs and IL-6 can directly affect glandular function.

IL-17 and IL-11 GCF levels in aggressive and chronic periodontitis patients: relation to PCR bacterial detection.

OBJECTIVES: This study evaluated IL-17 and IL-11 in gingival crevicular fluid (GCF) of generalized chronic periodontitis (GCP) and generalized aggressive periodontitis (GAgP) patients in relation to periodontopathic bacteria. SUBJECTS AND METHODS: GCF samples were collected from 65 subjects including 25 CP, 25 GAgP, and 15 controls (C) and analyzed for IL-17 and IL-11 by an enzyme-linked immunosorbent assay. Molecular detection of bacteria in the dental plaque was determined by polymerase chain reaction. RESULTS: The total amount of IL-17 was significantly higher in GAgP group than in GCP and C groups (P < 0.001). The IL-11 concentration was significantly higher in C and GCP groups than GAgP group (P < 0.001). The IL-11/IL-17 ratio was significantly higher in the C group than in GCP and GAgP groups (P < 0.05). Moreover, GAgP group showed lower ratios of IL-11/IL-17 when compared to GCP group. The high positivity of P. gingivalis in the dental plaque was associated with significantly increased GCF levels of IL-17 in GCP and GAgP patients. CONCLUSIONS: The increased IL-17 level in GCF of GAgP suggests a potential role in the aetiopathogenesis. Meanwhile, the decreased ratio of IL-11/IL-17 might reflect an imbalance between the proinflammatory and anti-inflammatory cytokines in different periodontal diseases.

Role of Interleukin-17A in the Pathomechanisms of Periodontitis and Related Systemic Chronic Inflammatory Diseases.

Periodontitis is a chronic inflammatory and destructive disease caused by periodontal microbial infection and mediated by host immune response. As the main cause of loosening and loss of teeth in adults, it is considered to be one of the most common and serious oral diseases in the world. The co-existence of periodontitis and systemic chronic inflammatory diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, diabetes and so on is very common. It has been found that interleukin-17A (IL-17A) secreted by various innate and adaptive immune cells can activate a series of inflammatory cascade reactions, which mediates the occurrence and development of periodontitis and related systemic chronic inflammatory diseases. In this work, we review the role of IL-17A in the pathomechanisms of periodontitis and related systemic chronic inflammatory diseases, and briefly discuss the therapeutic potential of cytokine targeted agents that modulate the IL-17A signaling. A deep understanding of the possible molecular mechanisms in the relationship between periodontitis and systemic diseases will help dentists and physicians update their clinical diagnosis and treatment ideas.

Interleukin-17: a novel inflammatory cytokine that bridges innate and adaptive immunity.

Interleukin-17 (IL-17A) is a pro-inflammatory cytokine that is primarily secreted from T lymphocytes, mediators of adaptive immunity. Recently, IL-17 was shown to be the defining cytokine of a new T helper subset termed "Th17." Discovery of the Th17 population was a groundbreaking discovery that has triggered major revisions of the prevailing paradigms in T cell biology. Although produced by T cells, IL-17 promotes expansion and recruitment of innate immune cells such as neutrophils, and also cooperates with TLR ligands, IL-1 beta, and TNF alpha to enhance inflammatory reactions and stimulate production of beta-defensins and other antimicrobial peptides. Its receptor, IL-17RA, is ubiquitously expressed and shares many features with classical innate immune receptors such as shared intracellular tail motifs and convergence on common inflammatory transcription pathways. The role of IL-17 in periodontal disease is still uncertain, since IL-17 has been shown to promote bone destruction in arthritis, but is nonetheless essential to protect the host from pathogens, including periodontopathic organisms. Recent evidence has shown that Th17 cells are more osteoclastogenic than other T helper subsets such as Th1 or Th2. Ablation of IL-17 signaling prior to onset of infection with Porphyromonas gingivalis increases susceptibility to periodontal bone loss, but this finding does not rule out the efficacy of therapeutic inhibition of IL-17 after onset of severe disease. IL-17 sits at the center of many complex diseases that integrate innate and adaptive immune mechanisms and requires careful study to maximize host protective effects and minimize host deleterious effects.

IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis.

IL-17 is a newly discovered T cell-derived cytokine whose role in osteoclast development has not been fully elucidated. Treatment of cocultures of mouse hemopoietic cells and primary osteoblasts with recombinant human IL-17 induced the formation of multinucleated cells, which satisfied major criteria of osteoclasts, including tartrate-resistant acid phosphatase activity, calcitonin receptors, and pit formation on dentine slices. Direct interaction between osteoclast progenitors and osteoblasts was required for IL-17-induced osteoclastogenesis, which was completely inhibited by adding indomethacin or NS398, a selective inhibitor of cyclooxgenase-2 (COX-2). Adding IL-17 increased prostaglandin E2 (PGE2) synthesis in cocultures of bone marrow cells and osteoblasts and in single cultures of osteoblasts, but not in single cultures of bone marrow cells. In addition, IL-17 dose-dependently induced expression of osteoclast differentiation factor (ODF) mRNA in osteoblasts. ODF is a membrane-associated protein that transduces an essential signal(s) to osteoclast progenitors for differentiation into osteoclasts. Osteoclastogenesis inhibitory factor (OCIF), a decoy receptor of ODF, completely inhibited IL-17-induced osteoclast differentiation in the cocultures. Levels of IL-17 in synovial fluids were significantly higher in rheumatoid arthritis (RA) patients than osteoarthritis (OA) patients. Anti-IL-17 antibody significantly inhibited osteoclast formation induced by culture media of RA synovial tissues. These findings suggest that IL-17 first acts on osteoblasts, which stimulates both COX-2-dependent PGE2 synthesis and ODF gene expression, which in turn induce differentiation of osteoclast progenitors into mature osteoclasts, and that IL-17 is a crucial cytokine for osteoclastic bone resorption in RA patients.

MMPs, IL-1, and TNF are regulated by IL-17 in periodontitis.

Periodontitis is characterized by periodontal tissue destruction. Since interleukin-17 (IL-17) has been reported to up-regulate IL-1beta and tumor necrosis factor-alpha (TNF-alpha), it was hypothesized that it is increased in periodontitis and up-regulates these cytokines and tissue-destructive matrix metalloproteinases (MMP) in local migrant and resident cells. Immunocytochemistry disclosed elevated IL-1beta, TNF-alpha, and IL-17 levels in periodontitis. These cytokines induced proMMP-1 and especially MMP-3 in gingival fibroblasts, whereas MMP-8 and MMP-9 were not induced. IL-17 was less potent as a direct MMP inducer than IL-1beta and TNF-alpha, but it induced IL-1beta and TNF-alpha production from macrophages, and IL-6 and IL-8 from gingival fibroblasts. In accordance with these findings, immunocytochemistry disclosed that MMP-1 and MMP-3 were increased in periodontitis. Gingival fibroblasts may play an important role in tissue destruction in periodontitis via cytokine-inducible MMP-1 and MMP-3 production, in which IL-17 plays a role as a key regulatory cytokine.

Interleukin-17 Impairs Salivary Tight Junction Integrity in Sjögren's Syndrome.

Sjögren's syndrome (SS) is an inflammatory autoimmune disease that causes secretory dysfunction of the salivary glands. It has been reported that proinflammatory cytokine interleukin-17 (IL-17) was elevated and tight junction (TJ) integrity disrupted in minor salivary glands from SS patients. However, whether the elevated IL-17 in SS affects TJ integrity and thereby alters the function of salivary gland is unknown. Here, by using nonobese diabetic (NOD) mice as SS model, we found that the stimulated salivary flow rate was significantly decreased in NOD mice. Lymphocyte infiltration was mainly observed in submandibular glands (SMGs), but not parotid glands (PGs), of NOD mice. IL-17 was significantly increased and mainly located in lymphocytic-infiltrating regions in SMGs but not detectable in PGs of NOD mice. Meanwhile, the epithelial barrier function was disrupted, as evidenced by an increased paracellular tracer clearance and an enlarged acinar TJ width in SMGs of NOD mice. Furthermore, claudin-1 and -3 were elevated especially at the basolateral membranes, whereas claudin-4, occludin, and zonula occludens-1 (ZO-1) were reduced in SMGs of NOD mice. Moreover, occludin and ZO-1 were dispersed into cytoplasm in SMGs of NOD mice. However, no change in the expression and distribution of TJ proteins was found in PGs. In vitro, IL-17 significantly decreased the levels and apical staining of claudin-4 and ZO-1 proteins in the cultured SMG tissues, as well as claudin-1, occludin, and ZO-1 in PG tissues. Moreover, IL-17 activated the phosphorylation of IκBα and p65 in SMG cells, whereas pretreatment with NF-κB inhibitor pyrrolidine dithiocarbamate suppressed the IL-17-induced downregulation of claudin-4 and ZO-1 in SMG tissues. Taken together, these findings indicate that IL-17 derived from infiltrating lymphocyte impairs the integrity of TJ barrier through NF-κB signaling pathway, and thus might contribute to salivary gland dysfunction in SS.

Nanotechnology-based drug delivery treatments and specific targeting therapy for age-related macular degeneration.

Nanoparticles combined with cells, drugs, and specially designed genes provide improved therapeutic efficacy in studies and clinical setting, demonstrating a new era of treatment strategy, especially in retinal diseases. Nanotechnology-based drugs can provide an essential platform for sustaining, releasing and a specific targeting design to treat retinal diseases. Poly-lactic-co-glycolic acid is the most widely used biocompatible and biodegradable polymer approved by the Food and Drug Administration. Many studies have attempted to develop special devices for delivering small-molecule drugs, proteins, and other macromolecules consistently and slowly. In this article, we first review current progress in the treatment of age-related macular degeneration. Then, we discuss the function of vascular endothelial growth factor (VEGF) and the pharmacological effects of anti-VEGF-A antibodies and soluble or modified VEGF receptors. Lastly, we summarize the combination of antiangiogenic therapy and nanomedicines, and review current potential targeting therapy in age-related macular degeneration.

Expression of IL-17B in neurons and evaluation of its possible role in the chromosome 5q-linked form of Charcot-Marie-Tooth disease.

IL-17B is a recently identified homolog of IL-17. Northern analysis revealed that IL-17B mRNA is expressed at very high levels in spinal cord and at much lower and more variable levels in trachea, prostate, lung, small intestine, testes, adrenal, and pancreas. In developing mouse embryos IL-17B expression was first detected at day 11 and appeared to peak at day 15. In situ analysis of mouse spinal cord, dorsal root ganglia, and brain demonstrated that IL-17B mRNA is primarily expressed by the neurons. Immunohistochemical analysis of human spinal cord, dorsal root ganglia, cerebral cortex, cerebellum, and hippocampus demonstrated that IL-17B protein is primarily localized to the neuronal cell bodies and axons. Radiation hybrid mapping localized the IL-17B gene to a region on human chromosome 5q that is associated with a rare autosomal recessive form of Charcot-Marie-Tooth demyelinating disease. However, no changes were found in the coding regions, splice junctions, intron 1, or the 5' and 3' untranslated regions of IL-17B genes of patients affected with this disease.

Porphyromonas gingivalis induces myocarditis and/or myocardial infarction in mice and IL-17A is involved in pathogenesis of these diseases.

OBJECTIVES: Although an association between periodontitis and cardiovascular diseases has been suggested, the role of Porphyromonas gingivalis in cardiovascular diseases is not clear. In this study, we examined whether experimental bacteremia of P. gingivalis causes cardiovascular diseases and investigated the mechanism of pathogenesis of cardiovascular diseases induced by P. gingivalis. DESIGN: C57BL/6 mice were intravenously inoculated with 2.0 × 10(8)CFU of P. gingivalis A7436 strain. Mice were sacrificed at specified days and their hearts were collected. The collected organs were divided into two halves and used for histological evaluation and cytokine analysis. IL-17A(-/-), IFN-γ(-/-) and TNF-α(-/-) mice were also intravenously inoculated and the histological changes of hearts in mice were examined. RESULTS: Myocarditis and/or myocardial infarction were observed in mice injected with P. gingivalis. The levels of IL1-ß, IL-6, IL-17A, IL-18, TNF-α and IFN-γ mRNA increased significantly after P. gingivalis injection. In particular, high levels of IL-17A and IFN-γ mRNA expression were observed in hearts of mice after P. gingivalis injection in comparison with these levels before injection. Furthermore, the production of IL-17A was detected in hearts of wild-type mice after P. gingivalis injection. In wild-type, TNF-α(-/-) and IFN-γ(-/-) mice, moderate infiltration of neutrophils and monocytes was observed in hearts at 5 days after injection. In contrast, no inflammatory findings were observed in hearts of IL-17A(-/-) mice. CONCLUSION: We have demonstrated that an experimental bacteremia of P. gingivalis could induce myocarditis and/or myocardial infarction in mice, and IL-17A plays an important role in the pathogenesis of these diseases.

IL-17A stimulates the expression of inflammatory cytokines via celecoxib-blocked prostaglandin in MC3T3-E1 cells.

OBJECTIVE: The prostaglandins (PGs) released from osteoblasts can alter the process of bone remodelling. Recently, we showed that compressive force induced the expression of pro-inflammatory cytokine interleukin (IL)-17s and their receptors in osteoblastic MC3T3-E1 cells and that IL-17A was expressed most highly. Consequently, in the current study we examined the effect of IL-17A and/or celecoxib on PGE(2) production and the expression of cyclooxygenases (COXs) and inflammatory cytokines in MC3T3-E1 cells. We also examined the effects of PGE(2) and cyclohexamide on the expression of inflammatory cytokines. METHODS: Cells were cultured with or without IL-17A (0.1, 1.0, or 10 ng/ml) in the presence or absence of 10 microM celecoxib, a specific inhibitor of COX-2, for up to 72 h. Cells were pretreated with or without 10 microg/ml cycloheximide, protein synthesis inhibitor, for 30 min, and then cultured with 10 ng/ml IL-17A for 24 h. Cells were also cultured with or without 1.5 ng/ml PGE(2) for 24 h. PGE(2) production was determined by ELISA. The expression of COX-1, COX-2, IL-1alpha, IL-6, IL-8, IL-11, and TNF-alpha mRNAs and proteins was determined by real-time PCR and ELISA, respectively. RESULTS: The expression of COX-2, IL-1alpha, IL-6, IL-8, IL-11, and TNF-alpha, as well as PGE(2) production increased in the presence of IL-17A, whereas COX-1 expression did not change. Celecoxib blocked the stimulatory effect of IL-17A on the expression of COX-2, IL-1alpha, IL-6, IL-8, and IL-11 as well as PGE(2) production, whereas it did not block TNF-alpha expression. Cycloheximide pretreatment suppressed the expression of IL-17-induced inflammatory cytokines. The expression of IL-1alpha, IL-6, IL-8, and IL-11 increased by the addition of PGE(2), whereas TNF-alpha expression was not affected. CONCLUSION: These results suggest that IL-17A stimulates the expression of bone resorption-related inflammatory cytokines through an autocrine mechanism involving celecoxib-blocked PGs, mainly PGE(2), in osteoblasts.

Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice.

Microbial colonization of mucosal surfaces may be an initial event in the progression to disease, and it is often a transient process. For the extracellular pathogen Streptococcus pneumoniae studied in a mouse model, nasopharyngeal carriage is eliminated over a period of weeks and requires cellular rather than humoral immunity. Here, we demonstrate that primary infection led to TLR2-dependent recruitment of monocyte/macrophages into the upper airway lumen, where they engulfed pneumococci. Pharmacologic depletion of luminal monocyte/macrophages by intranasal instillation of liposomal clodronate diminished pneumococcal clearance. Efficient clearance of colonization required TLR2 signaling to generate a population of pneumococcal-specific IL-17-expressing CD4+ T cells. Depletion of either IL-17A or CD4+ T cells was sufficient to block the recruitment of monocyte/macrophages that allowed for effective late pneumococcal clearance. In contrast with naive mice, previously colonized mice showed enhanced early clearance that correlated with a more robust influx of luminal neutrophils. As for primary colonization, these cellular responses required Th17 immunity. Our findings demonstrate that monocyte/macrophages and neutrophils recruited to the mucosal surface are key effectors in clearing primary and secondary bacterial colonization, respectively.

Interleukin-17 plays a role in exacerbation of inflammation within chronic periapical lesions.

Interleukin (IL)-17 plays an important role in inflammation and certain autoimmune diseases. However, its role in the pathogenesis of chronic dental periapical lesions has not been studied. Periapical lesion mononuclear cells (PL-MNC) were isolated from inflammatory cells and phenotypically analyzed by immunocytochemistry. The cells were cultured in vitro and IL-17 and IL-8 were measured in the culture supernatants. Controls were peripheral blood (PB) MNC. The level of IL-17 and the proportion of neutrophils were significantly higher in symptomatic lesions. In addition, the production of IL-17 was higher in culture supernatants of PL-MNC isolated from lesions with a predominance of T cells, and the IL-17 concentration correlated with the proportion of CD3+ and CD4+ cells. There was a positive correlation between the levels of IL-17 and IL-8 in the group of symptomatic lesions. The relationship between these cytokines was additionally confirmed on the basis of augmented production of IL-8 by both PL-MNC and PB-MNC treated with IL-17. Our results suggest that IL-17, by stimulating the production of IL-8, may play a role in exacerbating inflammation within chronic periapical lesions.

The potential role of interleukin-17 in the immunopathology of periodontal disease.

BACKGROUND: Interleukin-17 (IL-17) is exclusively produced by activated T cells, and this cytokine can induce inflammatory responses, support immune responses (Th1), and stimulate osteoclastic bone resorption in combination with receptor activator of NF-kappaB (RANK) and RANK ligand (RANKL). These biological functions are relevant to the aetiopathogenesis of periodontitis, and thus we sought to investigate whether IL-17 is produced in periodontal lesions and to assess the relationship of gene expression between IL-17 and other cytokines, and to determine the effect of IL-17 on IL-6 production in human gingival fibroblasts (HGF). MATERIALS AND METHODS: IL-17 was detected and measured in periodontal tissues obtained as biopsy samples during periodontal surgery and in the cell-free culture supernatants cultured ex vivo, by using Western immunoblotting and enzyme-linked immunosorbent assay, respectively. IL-17 and other cytokine gene expression were investigated by the reverse transcription-polymerase chain reaction (RT-PCR) method. The contribution of IL-17 to IL-6 production by HGF was studied. RESULTS: IL-17 protein was moderately detected in periodontal tissues. In contrast, IL-17 mRNA was expressed only in nine of 23 periodontitis tissue samples by RT-PCR. The IL-17 mRNA-positive samples simultaneously expressed mRNAs encoding interferon (IFN)-gamma, IL-2, RANK, and RANKL, but not IL-4. IL-10 (Th2 cytokine) was detected more frequently in the samples than IFN-gamma and IL-2 (Th1 cytokine). Recombinant human IL-17 induced IL-6 production from HGF in a dose- and time-dependent fashion. CONCLUSIONS: These results indicate that IL-17 is produced in periodontal lesions, which may be involved in Th1 modulation and enhance inflammatory reactions via gingival fibroblast-derived mediators in periodontal disease. Thus, IL-17, together with other cytokines, has a potential role in the aetiopathogenesis of periodontal disease.