Dataset Information

IL-6/IL-12 Cytokine Receptor Shuffling of Extra- and Intracellular Domains Reveals Canonical STAT Activation via Synthetic IL-35 and IL-39 Signaling.

ABSTRACT: IL-35 and IL-39 are recently discovered shared members of the IL-6- and IL-12-type cytokine family with immune-suppressive capacity. IL-35 has been reported to induce the formation of four different receptor complexes: gp130:IL-12?2, gp130:gp130, IL-12?2:IL-12?2, and IL-12?2:WSX-1. IL-39 was proposed to form a gp130:IL-23R receptor complex. IL-35, but not IL-39, has been reported to activate non-conventional STAT signaling, depending on the receptor complex and target cell. Analyses of IL-35 and IL-39 are, however, hampered by the lack of biologically active recombinant IL-35 and IL-39 proteins. Therefore, we engineered chimeric cytokine receptors to accomplish synthetic IL-35 and IL- 39 signaling by shuffling the extra- and intracellular domains of IL-6/IL-12-type cytokine receptors, resulting in biological activity for all previously described IL-35 receptor complexes. Moreover, we found that the proposed IL-39 receptor complex is biologically active and discovered two additional biologically active synthetic receptor combinations, gp130/IL-12R?1 and IL-23R/IL-12R?2. Surprisingly, synthetic IL-35 activation led to more canonical STAT signaling of all receptor complexes. In summary, our receptor shuffling approach highlights an interchangeable, modular domain structure among IL-6- and IL-12-type cytokine receptors and enabled synthetic IL-35 and IL-39 signaling.

SUBMITTER: Floss DM

PROVIDER: S-EPMC5680241 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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IL-6/IL-12 Cytokine Receptor Shuffling of Extra- and Intracellular Domains Reveals Canonical STAT Activation via Synthetic IL-35 and IL-39 Signaling.

Floss D M DM Schönberg M M Franke M M Horstmeier F C FC Engelowski E E Schneider A A Rosenfeldt E M EM Scheller J J

Scientific reports 20171109 1

IL-35 and IL-39 are recently discovered shared members of the IL-6- and IL-12-type cytokine family with immune-suppressive capacity. IL-35 has been reported to induce the formation of four different receptor complexes: gp130:IL-12β2, gp130:gp130, IL-12β2:IL-12β2, and IL-12β2:WSX-1. IL-39 was proposed to form a gp130:IL-23R receptor complex. IL-35, but not IL-39, has been reported to activate non-conventional STAT signaling, depending on the receptor complex and target cell. Analyses of IL-35 and ...[more]

PMID: 29123149

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Project description:Mycetoma is a neglected tropical disease, endemic in many tropical and subtropical regions, characterised by massive deformity and disability and can be fatal if untreated early and appropriately. Interleukins (IL) -35 and IL-37 are newly discovered cytokines that play an important role in suppressing the immune system. However, the expression of these interleukins in patients with Madurella mycetomatis (M. mycetomatis) induced eumycetoma has not yet been explored. The aim of this study is to determine the levels of IL-1 family (IL-1β, IL-37) and IL-12 family (IL-12, IL-35) in a group of these patients and the association between these cytokines levels and the patients' demographic characteristics. The present, case-control study was conducted at the Mycetoma Research Centre, Soba University Hospital, University of Khartoum, Sudan and it included 140 individuals. They were divided into two groups; group I: healthy controls [n = 70; median age 25 years (range 12 to 70 years)]. Group II: mycetoma patients [n = 70 patients; median age 25 (range 13 to 70 years)]. Cytokines levels were measured in sera using enzyme linked immunosorbent assay (ELISA). There was a significant negative correlation between IL-1β and IL-12 levels and lesion size and disease duration, while IL-37 and IL-35 levels were significantly positively correlated with both lesion size and disease duration. The analysis of the risk factors of higher circulatory levels of IL-37 in patients of mycetoma showed a negative significant association with IL-1β cytokine, where a unit increment in IL-1β will decrease the levels of IL-37 by 35.28 pg/ml. The levels of IL-37 among the patients with a duration of mycetoma infection ≤ 1 year were significantly low by an average of 18.45 pg/ml compared to patients with a mycetoma infection's duration of ≥ 5years (reference group). Furthermore, the risk factors of higher levels of IL-35 in mycetoma patients revealed a negative significant association with IL-12, as a unit increment in IL-12 decreases the levels of IL-35 by 8.99 pg/ml (p < 0.001). Levels of IL-35 among the patients with duration of mycetoma infection ≤ one year were significantly low on average by 41.82 pg/ml (p value = 0.002) compared to patients with a duration of mycetoma infection ≥ 5 years (reference group). In conclusion, this study indicates that both IL-35 and IL-37 are negatively associated with the levels of IL-1β and IL-12 in eumycetoma mycetoma infection; and high levels of IL-37 and IL-35 may have a negative impact on disease progression.

Project description:BackgroundIn this study, we have investigated the potential regulatory mechanisms of IL-35 to relieve lupus nephritis (LN) through regulating Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling pathway in mesangial cells.ResultsAmong 105 significant differentially expressed proteins (DEPs) between juvenile systemic lupus erythematosus (JSLE) patients with LN and healthy controls, LAIR1, PDGFRβ, VTN, EPHB4, and EPHA4 were downregulated in JSLE-LN. They consist of an interactive network with PTPN11 and FN1, which involved in IL-35-related JAK/STAT signaling pathway. Besides, urinary LAIR1 was significantly correlated with JSLE-LN clinical parameters such as SLEDAI-2K, %CD19+ B, and %CD3+ T cells. Through bioinformatics analysis of co-immunoprecipitation with mass spectrometry results, including GO, KEGG, and STRING, five genes interacted with Lair1 were upregulated by IL-35, but only Myh10 was downregulated. Therefore, we presumed an interactive network among these DEPs, JAK/STAT, and IL-35. Moreover, the downregulated phosphorylated (p)-STAT3, p-p38 MAPK, and p-ERK, and the upregulated p-JAK2/p-STAT1/4 in IL-35 overexpressed mesangial cells, and RNA-sequencing results validated the potential regulatory mechanisms of IL-35 in alleviating JSLE-LN disease. Moreover, the relieved histopathological features of nephritis including urine protein and leukocyte scores, a decreased %CD90+ αSMA+ mesangial cells and pro-inflammatory cytokines, the inactivated JAK/STAT signals and the significant upregulated Tregs in spleen, thymus and peripheral blood were validated in Tregs and IL-35 overexpression plasmid-treated lupus mice.ConclusionsOur study provided a reference proteomic map of urinary biomarkers for JSLE-LN and elucidated evidence that IL-35 may regulate the interactive network of LAIR1-PTPN11-JAK-STAT-FN1 to affect JAK/STAT and MAPK signaling pathways to alleviate inflammation in JSLE-LN. This finding may provide a further prospective mechanism for JSLE-LN clinical treatment.

Dataset Information

IL-6/IL-12 Cytokine Receptor Shuffling of Extra- and Intracellular Domains Reveals Canonical STAT Activation via Synthetic IL-35 and IL-39 Signaling.

Publications

IL-6/IL-12 Cytokine Receptor Shuffling of Extra- and Intracellular Domains Reveals Canonical STAT Activation via Synthetic IL-35 and IL-39 Signaling.

Similar Datasets

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