Integrated Signals Between IL-13, IL-4, and IL-5 Regulate Airways Hyperreactivity

Protein arginine methyltransferases (PRMTs), catalyzing methylation of both histones and other cellular proteins, have emerged as key regulators of various cellular processes. This study aimed to identify key PRMTs involved in Ag-induced pulmonary inflammation (AIPI), a rat model for asthma, and to explore the role of PRMT1 in the IL-4–induced eosinophil infiltration process. E3 rats were i.p. sensitized with OVA/alum and intranasally challenged with OVA to induce AIPI. The expressions of PRMT1–6, eotaxin-1, and CCR3 in lungs were screened by real-time quantitative PCR. Arginine methyltransferase inhibitor 1 (AMI-1, a pan-PRMT inhibitor) and small interfering RNA–PRMT1 were used to interrupt the function of PRMT1 in A549 cells. In addition, AMI-1 was administrated intranasally to AIPI rats to observe the effects on inflammatory parameters. The results showed that PRMT1 expression was mainly expressed in bronchus and alveolus epithelium and significantly upregulated in lungs from AIPI rats. The inhibition of PRMTs by AMI-1 and the knockdown of PRMT1 expression were able to downregulate the expressions of eotaxin-1 and CCR3 with the IL-4 stimulation in the epithelial cells. Furthermore, AMI-1 administration to AIPI rats can also ameliorate pulmonary inflammation, reduce IL-4 production and humoral immune response, and abrogate eosinophil infiltration into the lungs. In summary, PRMT1 expression is upregulated in AIPI rat lungs and can be stimulated by IL-4. Intervention of PRMT1 activity can abrogate IL-4–dependent eotaxin-1 production to influence the pulmonary inflammation with eosinophil infiltration. The findings may provide experimental evidence that PRMT1 plays an important role in asthma pathogenesis.

Section: Discussionmentioning

confidence: 99%

Upregulated Protein Arginine Methyltransferase 1 by IL-4 Increases Eotaxin-1 Expression in Airway Epithelial Cells and Participates in Antigen-Induced Pulmonary Inflammation in Rats

Sun

Yang

Zhong

et al. 2012

“…To examine whether the suppression of bronchial eosinophilia and airway hyperresponsiveness is consistent with local cytokine and chemokine patterns in the lung, we also analyzed the gene expression of major cytokines and chemokines in whole lung tissue using RT-PCR. Th2 cytokines such as IL-4, IL-5, and IL-13 and chemokines such as eotaxin were regarded as essential mediators for the development of bronchial eosinophilia and/or airway hyperresponsiveness (32)(33)(34)(35). Although the levels of IL-13 and eotaxin in the lung were remarkably decreased in OVA-fed mice before the first immunization (Fig.…”

Section: Figurementioning

confidence: 99%

Splenic Dendritic Cells Induced by Oral Antigen Administration Are Important for the Transfer of Oral Tolerance in an Experimental Model of Asthma

Nagatani

Dohi

et al. 2006

Peripheral tolerance can be induced after the feeding of Ag, which is referred to as oral tolerance. We demonstrated in this study that the oral administration of OVA induced tolerance in an experimental model of asthma in mice, and investigated which cells function as the regulatory cells in the transfer of this oral tolerance. In OVA-fed mice, the percentage of eosinophils in bronchoalveolar lavage fluid, serum IgE levels, airway hyperresponsiveness, and mRNA levels of IL-13 and eotaxin were significantly lower than found in nonfed mice. Histological examination of lung tissue showed a suppression of the accumulation of inflammatory cells in the peribronchial area of OVA-fed mice. Feeding after the first immunization or between the first and the second immunization suppressed these findings, whereas feeding just before the airway Ag challenge did not. The suppression of disease in OVA-fed mice was successfully transferred by injection of whole spleen cells of OVA-fed mice. When CD11c+ dendritic cells (DCs) were removed from splenocytes, this transfer of suppression was completely abolished. The injection of splenic DCs purified from OVA-fed mice alone transferred the suppression, whereas the injection of splenic DCs from naive mice that were cocultured with OVA in vitro did not. These data suggest that not only CD4+ T cells, but also CD11c+ DCs induced by Ag feeding are important for the active transfer of oral tolerance in this murine experimental model of asthma.

“…IL-4 Ϫ/Ϫ (27), IL-13 Ϫ/Ϫ (28,29), and IL-4R␣ Ϫ/Ϫ (30) mice were generated, as described, and bred at University of Manchester under specific pathogen-free conditions. All transgenic mice were on a BALB/c background.…”

Section: Animals and Infectionmentioning

confidence: 99%

Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection

McDermott

Humphreys

Forman

et al. 2005

IL-13 is a Th2-derived cytokine associated with pathological changes in asthma and ulcerative colitis. Moreover, it plays a major role in the control of gut nematode infection and associated immunopathology. The current paradigm is that these effects are due to T cell-derived IL-13. We show in this study that an innate source of IL-13, the intraepithelial NK cell, is responsible for the disruption of intestinal tissue architecture and induction of goblet cell hyperplasia that characterizes infection with the intestinal helminth Trichinella spiralis. IL-13 or IL-4Rα (but not IL-4) null mice failed to induce intestinal pathology. Unexpectedly, SCID and athymic mice developed the same pathology found in immunocompetent mice following infection. Moreover, immunodeficient mice expressed IL-13 in the intestine, and abnormal mucosal pathology was reduced by in vivo administration of a soluble IL-13 antagonist. IL-13 expression was induced in non-T intraepithelial CD3− NK cells. Epithelial cells expressed the IL-13 signaling receptor, IL-13Rα1, and after infection, IL-4Rα. Furthermore, the soluble IL-13 decoy receptor IL-13Rα2, which regulates IL-13 responses, was also induced upon infection. These data provide the first evidence that intestinal tissue restructuring during helminth infection is an innate event dependent on IL-13 production by NK cells resident in the epithelium of the intestine.