IL-35 Suppresses Lipopolysaccharide-Induced Airway Eosinophilia in EBI3-Deficient Mice

Kanai, Koomi; Park, Ah-Mee; Yoshida, Hiroki; Tsunoda, Ikuo; Yoshie, Osamu

doi:10.4049/jimmunol.1600506

Cited by 29 publications

(27 citation statements)

References 39 publications

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“…On the other hand, airway delivery of anti-IL35 significantly increased the number of eosinophils in the BALF from LPS-stimulated WT mice. This study demonstrated that IL-35 inhibits LPS-induced airway eosinophilia, at least in part by reducing the local production of CCL11 and CCL24 [28]. In our study, there was a significant increase in IL-35 level in the sputum of patients with NA.…”

Section: Discussionsupporting

confidence: 63%

“…Furthermore, there was a negative correlation between IL-35 and FEV1%, FeNO and a positive correlation between IL-35 and the number of neutrophils and IL-1-related (IL-1β, 6, and 8) inflammatory mediators. These findings suggest that IL-35 may play a key role in the infiltration and activity of eosinophils [28] and neutrophils [29] in asthma and may participate in the airway inflammation mechanism of asthma phenotypes. The function of IL-35 is complex and the results of different studies may be contradictory.…”

Section: Discussionmentioning

confidence: 81%

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Different expression levels of interleukin-35 in asthma phenotypes

Gao

Xin

et al. 2020

Respir Res

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Background: Interleukin (IL)-35 is a newly discovered inhibitory cytokine which is produced by regulatory B and T lymphocytes and belongs to the IL-12 family. It plays a suppressive role in human inflammatory diseases; however, its role in asthma phenotypes is unclear. Our study focuses on the sputum IL-35 level in patients and investigates different airway inflammation capacities of sputum IL-35 in patients with different asthma phenotypes. Objective: We aimed to determine the sputum IL-35 levels in asthmatic patients with clinical remission phenotypes and control subjects and to investigate possible correlations among lung function, age, sex, fractional exhaled nitric oxide (FeNO), and smoking history in these phenotypes. Methods: Sputum samples were collected from patients with clinical asthma remission (n = 89, 37 males, age 52.24 ± 13.32 years) and a healthy control group (n = 19, 9 males, age 44.58 ± 16.3 years). All subjects underwent sputum induction. Induced sputum was assessed for inflammatory cell count, and sputum levels of IL-35 and other cytokines were measured by ELISA and Cytometric Bead Array, respectively. Results: Sputum IL-35 (median (q1, q3)) levels showed no significant difference between asthma patients (4.89 ng/ mL (2.97, 22.75)) and healthy controls (6.01 ng/mL (4.09, 30.47)). However, the sputum IL-35 level was significantly reduced in patients with eosinophilic asthma (EA) (3.95 ng/mL (2.80, 11.00)) compared to patients with neutrophilic asthma (NA) (40.59 ng/mL (20.59, 65.06), p = 0.002), paucigranulocytic asthma (PA) (6.25 ng/mL (3.10, 24.60), p = 0.012), and mixed granulocytic asthma (MA) (22.54 ng/mL (2.58, 52.45), p = 0.026). IL-35 levels in sputum showed a positive correlation with sputum neutrophil cells and a negative correlation with FeNO, FEV1% predicted, and FVC predicted. Furthermore, sputum IL-35 had a significant positive association with Th1-related factors and a negative correlation with Th2-related factors. Conclusions: Sputum IL-35 is likely involved in different pathophysiological mechanisms of NA and EA and exerts different effects in asthma phenotypes.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 81%

Different expression levels of interleukin-35 in asthma phenotypes

Gao

Xin

et al. 2020

Respir Res

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“…Mice C57BL/6 mice were purchased from Japan SLC (Hamamatsu, Japan). IL-27-deficient mice (WSX1 -/and p28 -/mice) were described previously (11,41,42). Mice were housed and bred in a specific pathogen-free facility at Kindai University Faculty of Medicine and Tottori University Faculty of Medicine.…”

Section: Methodsmentioning

confidence: 99%

Murine γ-Herpesvirus 68 Induces Severe Lung Inflammation in IL-27–Deficient Mice with Liver Dysfunction Preventable by Oral Neomycin

Kanai

Park

Watanabe

et al. 2018

The Journal of Immunology

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IL-27 is an immunoregulatory cytokine consisting of p28 and EBI3. Its receptor also has two subunits, WSX1 and gp130. Although IL-27 promotes Th1 differentiation in naive T cells, it also induces IL-10 expression in effector Th1 cells to curtail excessive immune responses. By using p28-deficient mice and WSX1-deficient mice (collectively called IL-27-deficient mice), we examined the role of IL-27 in primary infection by murine γ-herpesvirus 68 (MHV68), a murine model of EBV. Upon airway infection with MHV68, IL-27-deficient mice had more aggravated lung inflammation than wild-type mice, although MHV68 infection per se was better controlled in IL-27-deficient mice. Although epithelial cells and alveolar macrophages were primarily infected by MHV68, interstitial macrophages and dendritic cells were the major producers of IL-27. The lung inflammation of IL-27-deficient mice was characterized by more IFN-γ-producing CD8 T cells and fewer IL-10-producing CD8 T cells than that of wild-type mice. An infectious mononucleosis-like disease was also aggravated in IL-27-deficient mice, with prominent splenomegaly and severe hepatitis. Infiltration of IFN-γ-producing effector cells and upregulation of the CXCR3 ligand chemokines CXCL9, CXCL10, and CXCL11 were noted in the liver of MHV68-infected mice. Oral neomycin effectively ameliorated hepatitis, with decreased production of these chemokines in the liver, suggesting that the intestinal microbiota plays a role in liver inflammation through upregulation of these chemokines. Collectively, IL-27 is essential for the generation of IL-10-producing effector cells in primary infection by MHV68. Our findings may also provide new insight into the mechanism of hepatitis associated with infectious mononucleosis.

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“…Increased eosinophils could be pathogenic in various diseases, such as eosinophilic pneumonias, allergic asthma, and eosinophil‐associated gastrointestinal disorders . Recent findings suggest that IL‐35 decreases airway eosinophilia by reducing the production of the eosinophil‐attracting chemokines CCL11 and CCL24, which demonstrates that IL‐35 may provide a new therapeutic strategy to reduce tissue recruitment of eosinophils in such diseases . In addition, studies have shown that the expression of IL‐35 is down‐regulated in chronic obstructive pulmonary disease, a chronic bronchitis and emphysema characterized by airflow obstruction .…”

Section: Il‐35 and Immune‐related Diseasesmentioning

confidence: 99%

“…65,66 Recent findings suggest that IL-35 decreases airway eosinophilia by reducing the production of the eosinophil-attracting chemokines CCL11 and CCL24, which demonstrates that IL-35 may provide a new therapeutic strategy to reduce tissue recruitment of eosinophils in such diseases. 67 In addition, studies have shown that the expression of IL-35 is down-regulated in chronic obstructive pulmonary disease, a chronic bronchitis and emphysema characterized by airflow obstruction. 68 Moreover, decreased IL-35 levels were negatively correlated with the smoking status, indicating that IL-35 can serve as a biomarker to estimate progression of chronic obstructive pulmonary disease.…”

Section: Il-35 and Allergic Airway Diseasementioning

confidence: 99%

Interleukin‐35 in immune‐related diseases: protection or destruction

Zhang

Wang

et al. 2019

Immunology

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Summary Interleukin‐35 (IL‐35) is a recently identified heterodimeric cytokine in the IL‐12 family. It consists of an IL‐12 subunit α chain (P35) and IL‐27 subunit Epstein–Barr virus‐induced gene 3 (EBI3) β chain. Unlike the other IL‐12 family members, it signals through four unconventional receptors: IL‐12Rβ2–IL‐27Rα, IL‐12Rβ2–IL‐12Rβ2, IL‐12Rβ2–GP130, and GP130–GP130. Interleukin‐35 signaling is mainly carried out through the signal transducer and activator of transcription family of proteins. It is secreted not only by regulatory T (Treg) cells, but also by CD8+ Treg cells, activated dendritic cells and regulatory B cells. It exhibits immunosuppressive functions distinct from those of other members of the IL‐12 family; these are mediated primarily by the inhibition of T helper type 17 cell differentiation and promotion of Treg cell proliferation. Interleukin‐35 plays a critical role in several immune‐associated diseases, such as autoimmune diseases and viral and bacterial infections, as well as in tumors. In this review, we summarize the structure and function of IL‐35, describe its role in immune‐related disorders, and discuss the mechanisms by which it regulates the development and progression of diseases, including inflammatory bowel disease, collagen‐induced arthritis, allergic airway disease, hepatitis, and tumors. The recent research on IL‐35, combined with improved techniques of studying receptors and signal transduction pathways, allows for consideration of IL‐35 as a novel immunotherapy target.

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IL-35 Suppresses Lipopolysaccharide-Induced Airway Eosinophilia in EBI3-Deficient Mice

Cited by 29 publications

References 39 publications

Different expression levels of interleukin-35 in asthma phenotypes

Different expression levels of interleukin-35 in asthma phenotypes

Murine γ-Herpesvirus 68 Induces Severe Lung Inflammation in IL-27–Deficient Mice with Liver Dysfunction Preventable by Oral Neomycin

Interleukin‐35 in immune‐related diseases: protection or destruction

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