IL-35 is elevated in clinical and experimental sepsis and mediates inflammation

Cao, Ju; Xu, Fang; Lin, Shihui; Tao, Xintong; Yu, Xiang; Lai, Xiaofei; Zhang, Liping

doi:10.1016/j.clim.2015.08.016

Cited by 34 publications

(26 citation statements)

References 33 publications

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“…Human IL-35 expression has been reported in chronic hepatitis B virus-infected patients [31], normal pregnancies [32], sepsis [33], and rheumatoid arthritis [34]. In support of a mathematical modeling analysis that reported a correlation between IL-35 and tumors [16], we demonstrate that elevated IL-35 level in CRC patients is coincident with an increase in Treg cells and it was mainly expressed in CD4 + T cells in human colorectal cancer and adjacent tissues.…”

Section: Discussionmentioning

confidence: 99%

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

Chen

Xie

et al. 2016

Oncotarget

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IL-35 is a novel heterodimeric and inhibitory cytokine, composed of interleukin-12 subunit alpha (P35) and Epstein-Barr virus -induced gene 3 (EBI3). IL-35 has been reported to be produced by a range of cell types, especially regulatory T cells, and to exert immunosuppressive effects via the STATx signaling pathway. In this study, we demonstrated that IL-35 expression was elevated in both serum and tumors in patients with colorectal cancer. IL-35 mainly expressed in CD4+ T cells in human colorectal cancer tumors and adjacent tissues. Increased IL-35 expression in tumor-adjacent tissues was significantly associated with tumor metastasis. IL-35 inhibited the proliferation of CD4+CD25− T effector cells in vitro in a dose-dependent manner, and its suppression was partially reversed by applying IL-35-neutralizing antibodies. IL-35 treatment activated the phosphorylation of both STAT1 and STAT3 in human CD4+ T cells. Meanwhile, IL-35 induced a positive feedback loop to promote its own production. We observed that Tregs obtained from colorectal cancer patients were capable of inducing more IL-35 production. In addition, EBI3 promoter-driven luciferase activity was higher than that of the mock plasmid after IL-35stimulation. Thus, our study indicates that the high level of IL-35 in colorectal cancer promotes the production of IL-35 via STAT1 and STAT3, which suppresses T cell proliferation and may participate in tumor immunotolerance.

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Section: Discussionmentioning

confidence: 99%

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

Chen

Xie

et al. 2016

Oncotarget

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“…In the present study, IL-35 levels in septic and neonates hospitalized newborns were compared to determine the predictive value of IL-35 as a biomarker in the diagnosis of NEOS. To our knowledge, there are very few investigations to assess this correlation [13,14]. Our results demonstrated that the mean IL-35 in serum samples from septic neonates was significantly higher than this mediator in unlikely infected neonates (13.41 ± 2.4, 9.02 ± 2.6; p = 0.0001).…”

Section: Discussionmentioning

confidence: 59%

“…Cao et al have reported that serum levels of IL-35 in septic patients were significantly higher than this factor among their healthy counterparts. They also showed that the rise of serum concentration of IL-35 was consistent with the level of sepsis severity [14]. Machado et al reported that proinflammatory and anti-inflammatory cytokines could be a probable biomarker for neonatal sepsis.…”

Section: Introductionmentioning

confidence: 78%

Assessment of serum interleukin-35 as a diagnostic biomarker of neonatal early-onset sepsis

et al. 2019

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Neonatal sepsis is a life-threatening disorder among infants, which is associated with high morbidity and mortality. In recent years, although the management of newborns has improved, early diagnosis and treatment of neonatal earlyonset sepsis (NEOS) are the major challenges for neonatologists in Neonatal intensive care units (NICUs). We assessed the diagnostic value of interleukins-35 (IL-35) in diagnosis of NEOS. A prospective process evaluation study was carried out in the NICU of Akbar-Abadi and Ali-Asghar Hospitals affiliated to Iran University of Medical Sciences from 2017 to 2018. Eighty hospitalized neonates with clinical suspicion of sepsis in the first 72 h of life entered the study by convenience or accidental sampling. Routine hematology tests regarding sepsis diagnosis were performed after admission. All subjects were assigned into two groups: newborns with proven sepsis and newborns with suspected sepsis. IL-35 levels in septic and unlikely infected hospitalized newborns were measured using Elisa Kit (ZellBio GmbH. Cat. No; ZB-10042C-H9648, Human Interleukin 35), and the results were compared. The mean IL-35 in serum samples from septic neonates was significantly higher than this variable in samples from unlikely infected newborns (13.41 ± 2.4 vs. 9.02 ± 2.6 pg/ml; p < 0.0001). The area under receiver-operating characteristic (ROC) curve for IL-35 was 0.895 (CI 95% = 0.826-0.963; p = 0.0001). The result of study showed serum IL-35 had a moderate accuracy (AUC = 0.895) for the diagnosis of NS. Therefore, serum IL-35 could be suggested as a predictive biomarker in neonatal early-onset sepsis. Further studies with larger sample size are strongly suggested.

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“…Moreover, administration of anti-IL-35 antibodies diminished dissemination of the bacteria in septic animals and enhanced local neutrophil recruitment with increases in inflammatory cytokines and chemokines production [43]. Furthermore, IL-35 suppressed the proliferation of antigen-specific CTLs and IFN-γ production [64].…”

Section: Discussionmentioning

confidence: 99%

“…In bacterial infections, Shen and associates [35] found that mice without IL-35 expression demonstrated an improved resistance to infection with the intracellular bacterial pathogen Salmonella typhimurium . In addition, IL-35 has been increased in the serum of adults and children with sepsis, and administration of anti-IL-35 p35 antibodies diminished dissemination of the bacteria in septic animals [43]. Similarly, tuberculous patients exhibited an increase in serum IL-35 and in mRNA expression of both subunits of IL-35 (p35 and EBI3) in white blood cells and peripheral blood mononuclear cells [44].…”

Section: Introductionmentioning

confidence: 99%

The Role of Interleukin-1 cytokine family (IL-1β, IL-37) and interleukin-12 cytokine family (IL-12, IL-35) in eumycetoma infection pathogenesis

Fahal

Abushouk²,

Masuadi

et al. 2018

Preprint

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48Mycetoma is a neglected tropical disease, endemic in many tropical and subtropical regions, 49 characterised by massive deformity and disability and can be fatal if untreated early and 50 appropriately. Interleukins (IL) -35 and IL-37 are newly discovered cytokines that play an 51 important role in suppressing the immune system. However, the expression of these 52 interleukins in patients with Madurella mycetomatis (M. mycetomatis) induced eumycetoma 53 has not yet been explored. This study aims to determine the levels of the IL-1 family (IL-1β, 54 IL-37) and IL-12 family (IL-12, IL-35) in a group of these patients and the association 55 between these cytokines levels and the patients' demographic characteristics. The present, 56 a case-control study was conducted at the Mycetoma Research Centre, Soba University 57 Hospital, University of Khartoum, Sudan and it included 140 individuals. They were divided 58 into two groups; group I: healthy controls [n = 70; median age 25 years (range 12 to 70 59 years)]. Group II: mycetoma patients [n = 70 patients; median age 25 (range 13 to 70 60 years)]. Cytokines levels were measured in sera using enzyme-linked immunosorbent assay 61 (ELISA). 62 There was no significant correlation between the IL-1β and IL-12 levels and the lesions size 63 and disease duration, whereas levels of IL-37 and IL-35 were significantly correlated with 64 that. The analysis of the risk factors of higher circulatory levels of IL-37 in patients of 65 mycetoma showed a significant negative association with IL-1β cytokine, where a unit 66 increment in IL-1β will decrease the levels of IL-37 by 35.28 pg/ml. The levels of IL-37 67 among the patients with a duration of mycetoma infection ≤ one year had significantly 68 decreased by an average of 18.45 compared to patients with a mycetoma infection's 69 duration of ≥ 5years (reference group). Furthermore, the risk factors of higher levels of IL-35 . CC-BY 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/502609 doi: bioRxiv preprint 70 in mycetoma patients revealed a significant negative association with IL-12, as a unit 71 increment in IL-12 decreases the levels of IL-35by 8.99 pg/ml (p < 0.001). Levels of IL-35 72 among the patients with duration of mycetoma infection ≤ one year had significantly 73 decreased (p-value = 0.002) on average by 41.82 compared to patients with a duration of 74 mycetoma infection ≥ five years (reference group). In conclusion, this study indicates that 75 both IL-35 and IL-37 are negatively associated with the levels of IL-1β and IL-12 in 76 eumycetoma mycetoma infection; and high levels of IL-37 and IL-35 may have a negative 77 impact on disease progression. 78 79 Authors Summary 80 Mycetoma is a progressive chronic granulomatous fungal or bacterial infection that may 81 result in massive destruction of subcutaneous tissues, muscles and bones. Mycetoma is 82 a neglected disease which is endemic in many...

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IL-35 is elevated in clinical and experimental sepsis and mediates inflammation

Cited by 34 publications

References 33 publications

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

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

Assessment of serum interleukin-35 as a diagnostic biomarker of neonatal early-onset sepsis

The Role of Interleukin-1 cytokine family (IL-1β, IL-37) and interleukin-12 cytokine family (IL-12, IL-35) in eumycetoma infection pathogenesis

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