Dataset Information

IL-1 and IL-23 mediate early IL-17A production in pulmonary inflammation leading to late fibrosis.

ABSTRACT:

Background

Idiopathic pulmonary fibrosis is a devastating as yet untreatable disease. We demonstrated recently the predominant role of the NLRP3 inflammasome activation and IL-1? expression in the establishment of pulmonary inflammation and fibrosis in mice.

Methods

The contribution of IL-23 or IL-17 in pulmonary inflammation and fibrosis was assessed using the bleomycin model in deficient mice.

Results

We show that bleomycin or IL-1?-induced lung injury leads to increased expression of early IL-23p19, and IL-17A or IL-17F expression. Early IL-23p19 and IL-17A, but not IL-17F, and IL-17RA signaling are required for inflammatory response to BLM as shown with gene deficient mice or mice treated with neutralizing antibodies. Using FACS analysis, we show a very early IL-17A and IL-17F expression by ROR?t(+) ?? T cells and to a lesser extent by CD4??(+) T cells, but not by iNKT cells, 24 hrs after BLM administration. Moreover, IL-23p19 and IL-17A expressions or IL-17RA signaling are necessary to pulmonary TGF-?1 production, collagen deposition and evolution to fibrosis.

Conclusions

Our findings demonstrate the existence of an early IL-1?-IL-23-IL-17A axis leading to pulmonary inflammation and fibrosis and identify innate IL-23 and IL-17A as interesting drug targets for IL-1? driven lung pathology.

SUBMITTER: Gasse P

PROVIDER: S-EPMC3156735 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Publications

IL-1 and IL-23 mediate early IL-17A production in pulmonary inflammation leading to late fibrosis.

Gasse Paméla P Riteau Nicolas N Vacher Rachel R Michel Marie-Laure ML Fautrel Alain A di Padova Franco F Fick Lizette L Charron Sabine S Lagente Vincent V Eberl Gérard G Le Bert Marc M Quesniaux Valérie F J VF Huaux François F Leite-de-Moraes Maria M Ryffel Bernhard B Couillin Isabelle I

PloS one 20110816 8

<h4>Background</h4>Idiopathic pulmonary fibrosis is a devastating as yet untreatable disease. We demonstrated recently the predominant role of the NLRP3 inflammasome activation and IL-1β expression in the establishment of pulmonary inflammation and fibrosis in mice.<h4>Methods</h4>The contribution of IL-23 or IL-17 in pulmonary inflammation and fibrosis was assessed using the bleomycin model in deficient mice.<h4>Results</h4>We show that bleomycin or IL-1β-induced lung injury leads to increased ...[more]

PMID: 21858022

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Project description:BackgroundDental implantation has been practiced since ancient times and has gone through several stages. Dentists use dental implants to support dental prostheses such as crowns, bridges, dentures, face prostheses, or as an orthodontic anchor. Thus, the purpose of this study is to detect the role of the immune-genetic variation of IL-17A and related inflammatory cytokine (IL-23) in the initiation and progress of peri implantitis.Material and methodsThis cross-sectional study included 80 subjects (15 peri-implantitis patients, 35 successful implants, and 30 healthy controls); their mean age was (43.91 ± 11.33) years. Blood samples and Peri-implant sulcus fluid (PISF) were collected from all subjects (patients with peri-implantitis, successful implants, and healthy controls) attending the Department of Oral and Maxillofacial Surgery in the Dental College Teaching Hospital, Baghdad University, Baghdad, Iraq. The blood sample detects gene polymorphisms in interleukin-17A by a polymerase chain reaction (PCR). An enzyme-linked immunosorbent assay (ELISA) was carried out to estimate the Peri-implant sulcus fluid (PISF) levels of interleukin-23.ResultThe current study revealed an obvious significant elevation in the mean level of interleukin-23 in the peri-implantitis patient's group more than its level in the successful implant and control groups (P < 0.05). In addition, the result showed that A/A genotype is associated significantly with peri-implantitis OR (95%confidence interval) =6.9 (1.7121 to 27.4638) folds increase risk of peri-implantitis) (p = 0.0065), while G/A genotype had OR 4.9 (0.9539-24.9394) folds increased risk of peri-implantitis, (p = 0.0572). But it was not statistically significant and G/G genotype had a one-fold increase risk of peri-implantitis.ConclusionThe increased level of inflammatory cytokine (interleukin-23) might add to the systemic inflammatory burden a predisposing factor, which may lead to impaired osseointegration and subsequent bone loss or implant failure. In addition, IL-17A gene polymorphism may play a role in peri-implant disease susceptibility, especially in persons carrying the rs2275913 A allele at a higher risk of developing peri-implantitits as compared with those carrying the G allele.

Project description:BackgroundInterstitial lung disease, a common extra-articular complication of connective tissue disease, is characterized by progressive and irreversible pulmonary inflammation and fibrosis, which causes significant mortality. IL-22 shows a potential in regulating chronic inflammation and possibly plays an anti-fibrotic role by protecting epithelial cells. However, the detailed effects and underlying mechanisms are still unclear. In this study, we explored the impact of IL-22 on pulmonary fibrosis both in vivo and in vitro.MethodsTo induce pulmonary fibrosis, wild-type mice and IL-22 knockout mice were intratracheally injected with bleomycin followed by treatments with recombinant IL-22 or IL-17A neutralizing antibody. We investigated the role of IL-22 on bleomycin-induced pulmonary fibrosis and the mechanism in the possible interaction between IL-22 and IL-17A. Fibrosis-related genes were detected using RT-qPCR, western blot, and immunofluorescence. Inflammatory and fibrotic changes were assessed based on histological features. We also used A549 human alveolar epithelial cells, NIH/3T3 mouse fibroblast cells, and primary mouse lung fibroblasts to study the impact of IL-22 on fibrosis in vitro.ResultsIL-22 knockout mice showed aggravated pulmonary fibrosis compared with wild-type mice, and injection of recombinant IL-22 decreased the severe fibrotic manifestations in IL-22 knockout mice. In cell culture assays, IL-22 decreased protein levels of Collagen I in A549 cells, NIH/3T3 cells, and primary mouse lung fibroblasts. IL-22 also reduced the protein level of Collagen I in NIH/3T3 cells which were co-cultured with T cells. Mechanistically, IL-22 reduced the Th17 cell proportion and IL-17A mRNA level in lung tissues, and treatment with an IL-17A neutralizing antibody alleviated the severe pulmonary fibrosis in IL-22 knockout mice. The IL-17A neutralizing antibody also reduced Collagen I expression in NIH/3T3 cells in vitro. Knockdown of IL-17A with siRNAs or administration of IL-22 in NIH/3T3 cells and MLFs decreased expression of Collagen I, an effect blocked by concurrent use of recombinant IL-17A.ConclusionsIL-22 mediated an anti-fibrogenesis effect in the bleomycin-induced pulmonary fibrosis model and this effect was associated with inhibition of IL-17A.

Dataset Information

IL-1 and IL-23 mediate early IL-17A production in pulmonary inflammation leading to late fibrosis.

Background

Methods

Results

Conclusions

Publications

IL-1 and IL-23 mediate early IL-17A production in pulmonary inflammation leading to late fibrosis.

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