Elevated level of Interleukin-35 in colorectal cancer induces conversion of T cells into iTr35 by activating STAT1/STAT3

Ma, Yonggang; Chen, Lei; Xie, Guohua; Zhou, Yunli; Yue, Chaoyan; Yuan, Xiangliang; Zheng, Yingxia; Wang, Weiwei; Deng, Lin; Shen, Lisong

doi:10.18632/oncotarget.12193

Cited by 49 publications

(46 citation statements)

References 37 publications

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“…Interleukin-35 (IL-35) is a newly discovered member of the interleukin family with anti-inflammatory and immune inhibitory effects [7,8]. Recently, it has been demonstrated that IL-35 plays an important role in tumor progression, including lung cancer [9], pancreatic cancer [10], nasopharyngeal carcinoma [11], gastric cancer [12], hepatocellular carcinoma [13][14][15], breast cancer [16,17], renal cell carcinoma [18] and colorectal cancer [19,20]. However, the underlying mechanisms of IL-35 in NSCLC remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-35 Expression in Non-Small Cell Lung Cancer is Associated with Tumor Progression

Sun¹,

Zheng²,

Meng³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Lung cancer continues to be the leading cause of cancer related deaths worldwide due to its high incidence, malignant behavior and lack of major advancements in treatment strategy. The occurrence and development of lung cancer is closely related to inflammation. Thus, we conducted the present study to investigate the effects of IL-35 (Interleukin 35), a newly identified anti-inflammatory factor, on non-small cell lung cancer (NSCLC), which accounts for about 85% of all lung cancers. Methods: We first evaluated the IL-35 expression in 384 pairs of NSCLC samples and their adjacent normal mucosa by realtime PCR, ELISA (Enzyme-linked immunoassay) and tissue microarrays. Then the role of IL-35 on patient survival rates, cancer progression and their sensitivity to chemotherapy drugs were assessed. Results: IL-35 was barely expressed in the NSCLC tissues but highly expressed in the adjacent normal tissues. The down-regulation of IL-35 was significantly correlated with the results of American Joint Committee on Cancer stage, differentiation and it was also shown to be an independent prognostic indicator of disease-free survival and overall survival for patients with NSCLC. Overexpression of IL-35 in NSCLC cells suppressed cell migration, invasion, proliferation, colony formation through suppressing β-catenin. IL-35 inhibited NSCLC formation in the mice model and sensitize the cancer cells to chemotherapy drugs. Conclusion: Our results showed that IL-35 plays an inhibitory role in NSCLC development and function as a novel prognostic indicator and a potential therapeutic target.

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Section: Introductionmentioning

confidence: 99%

Interleukin-35 Expression in Non-Small Cell Lung Cancer is Associated with Tumor Progression

Sun¹,

Zheng²,

Meng³

et al. 2018

Cell Physiol Biochem

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“…Signaling through IL-35 results in the suppression of Janus kinase/signal transducer and activator of transcription pathway [15,16]. Thus, IL-35 always inhibits T cell proliferation and converts naïve T cells into IL-35secreting induced regulatory T cells [17,18]. Importantly, IL-35 dampens inflammatory process and prevents coronary artery lesion in patients with Kawasaki disease [19].…”

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confidence: 99%

Increased Interleukin-35 suppresses peripheral CD14+ monocytes function in patients with Kawasaki disease

Xing

Tian

2020

BMC Immunol

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Background: Interleukin-35 (IL-35) is a newly identified IL-12 cytokine family member, which regulates the activity of immune cells in infectious diseases and autoimmune disorders. However, the regulatory function of IL-35 in Kawasaki disease is not well elucidated. Methods: Thirty-three patients with Kawasaki disease and seventeen healthy controls were studied. Peripheral IL-35 concentration was measured by enzyme linked immunosorbent assay. CD14 + monocytes were purified, and mRNA expression of IL-35 receptor (IL-12Rβ2 and gp130) was semi-quantified by real-time polymerase chain reaction. CD14 + monocytes were stimulated with recombinant IL-35. The modulatory role of IL-35 treated CD14 + monocytes to naïve CD4 + T cell activation was investigated by flow cytometry. The influence of IL-35 to cytotoxicity of CD14 + monocytes was assessed by measuring target cell death, cytokine and granzyme secretion.Results: Plasma IL-35 concentration was elevated in patients with Kawasaki disease. There was no significant differences of either IL-12Rβ2 or gp130 mRNA expression in CD14 + monocytes between Kawasaki disease patients and controls. IL-35 suppressed CD14 + monocytes induced naïve CD4 + T cell activation in Kawasaki disease, and this process required direct cell-to-cell contact. IL-35 also inhibited tumor necrosis factor-α and granzyme B secretion by CD14 + monocytes from patients with Kawasaki disease, however, only granzyme B was responsible for the cytotoxicity of CD14 + monocytes.Conclusions: IL-35 played an important immunosuppressive role to CD14 + monocytes function in Kawasaki disease.

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“…Studies also demonstrated that IL‐35 expression was elevated in both serum and tumors in patients with colorectal cancer. These elevated IL‐35 can suppress T‐cell proliferation and may participate in tumor immunotolerance . However, Zhang et al .…”

Section: Il‐35 and Immune‐related Diseasesmentioning

confidence: 99%

“…These elevated IL-35 can suppress T-cell proliferation and may participate in tumor immunotolerance. 91 endothelial growth factor-induced ANG2 and disturbing ANG2/TIE2 signaling. 93 Conversely, IL-35 produced by tumor cells can promote tumor growth by promoting the recruitment of CD11b + GR1 + myeloid-derived suppressor cells and increase angiogenesis in the tumor microenvironment.…”

Section: Il-35 and Tumorsmentioning

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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Elevated level of Interleukin-35 in colorectal cancer induces conversion of T cells into iTr35 by activating STAT1/STAT3

Cited by 49 publications

References 37 publications

Interleukin-35 Expression in Non-Small Cell Lung Cancer is Associated with Tumor Progression

Interleukin-35 Expression in Non-Small Cell Lung Cancer is Associated with Tumor Progression

Increased Interleukin-35 suppresses peripheral CD14+ monocytes function in patients with Kawasaki disease

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

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