IL-30† (IL-27A): a familiar stranger in immunity, inflammation, and cancer

Min, Booki; Kim, Dongkyun; Feige, Matthias J.

doi:10.1038/s12276-021-00630-x

Cited by 18 publications

(14 citation statements)

References 104 publications

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“…In this study, we found that the administration of AAV-mIL-30 decreased the activation and IFN-γ production of CD4 + T cells in autoimmune cholangitis. This result is similar to that of previous studies where the administration of IL-30-encoding plasmids decreases the intrinsic ability of CD4 + T cells to produce IFN-γ and where IL-30 conditional knockout mice produce extremely high levels of IFN-γ when injected with ConA [20,21]. However, the immunosuppressive function of IL-30 has been reported in autoimmune diseases such as experimental autoimmune encephalomyelitis and experimental autoimmune uveitis [22,23], though not in liver autoimmune diseases.…”

Section: Discussionsupporting

confidence: 90%

Interleukin-30 Suppresses Not Only CD4+ T Cells but Also Regulatory T Cells in Murine Primary Biliary Cholangitis

2021

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Primary biliary cholangitis (PBC) is a chronic liver autoimmune disease with augmented T helper (Th) 1 and corresponding cytokine IFN-γ immune responses. Using 2-octynoic acid (2-OA) coupled to OVA (2-OA-OVA)-induced mouse models of autoimmune cholangitis (inducible chemical xenobiotic models of PBC), our previous study demonstrated that overexpression of IFN-γ in the model mice enhanced liver inflammation upon disease initiation, but subsequently led to the suppression of chronic inflammation with an increase in interleukin-30 (IL-30) levels. In this study, we investigated whether IL-30 had an immunosuppressive function and whether it could be part of an immune therapeutic regimen for PBC, by treating model mice with murine IL-30-expressing recombinant adeno-associated virus (AAV-mIL-30). We first defined the effects of AAV-mIL-30 in vivo by administering it to a well-known concanavalin A (ConA)-induced hepatitis model of mice and found that AAV-mIL-30 reduced the numbers of activated CD25+CD4+ T cells and the levels of serum IFN-γ and IL-12. In autoimmune cholangitis, decreased numbers of activated CD4+ T cells and Foxp3+ regulatory T cells were noted in the mice treated with AAV-mIL-30 at 3 weeks after the 2-OA-OVA immunization. Treatment with IL-30 did not change the features of autoimmune cholangitis including autoantibodies, cell infiltration, and collagen deposition in the liver at 11 weeks of examination. However, increased levels of cytokines and chemokines were observed. These results suggest that IL-30 suppresses not only CD4+ T cells but also regulatory T cells. Additionally, the administration of IL-30 did not suppress liver inflammation in the murine model of PBC.

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Section: Discussionsupporting

confidence: 90%

Interleukin-30 Suppresses Not Only CD4+ T Cells but Also Regulatory T Cells in Murine Primary Biliary Cholangitis

2021

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“…The emergence of IL-27p28, as either a standalone cytokine subunit (that has been labeled IL-30) or one that can pair with soluble receptors other than EBI3 (and create alternative signaling complexes), has drastically expanded the range of immunomodulatory functions for IL-27-related proteins and their expanded roles in physiology and disease ( Min et al., 2021 ). The structural models at high resolution we present here for mouse and human IL-27p28 (IL-30) will undoubtedly help to produce redesigned p28 monomers that could clarify IL-30 biology and its pairing with other receptor subunits.…”

Section: Discussionmentioning

confidence: 99%

Structural basis of activation and antagonism of receptor signaling mediated by interleukin-27

Składanowska

Bloch

Strand³

et al. 2022

Cell Reports

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“…Indeed, another chaperonelike activity of EBI3 was reported for formation of IL-27 (30,31). In mice, p28, also designated as IL-30, is secreted and exerts immunoregulatory roles (41), while human p28 is not autonomously secreted due to the difference in one amino acid residue cysteine that is necessary for disulfide bond formation (30). Without EBI3 human p28 is retained and becomes degraded by the ER quality control machinery, whereas the presence of EBI3 facilitates the proper protein folding, leading to efficient secretion of human p28 and formation of IL-27 heterodimer.…”

Section: Ebi3 Facilitates the Proper Protein Folding Of P28 To Form Il-27mentioning

confidence: 99%

A Chaperone-Like Role for EBI3 in Collaboration With Calnexin Under Inflammatory Conditions

et al. 2021

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The interleukin-6 (IL-6)/IL-12 family of cytokines plays critical roles in the induction and regulation of innate and adaptive immune responses. Among the various cytokines, only this family has the unique characteristic of being composed of two distinct subunits, α- and β-subunits, which form a heterodimer with subunits that occur in other cytokines as well. Recently, we found a novel intracellular role for one of the α-subunits, Epstein-Barr virus-induced gene 3 (EBI3), in promoting the proper folding of target proteins and augmenting its expression at the protein level by binding to its target protein and a well-characterized lectin chaperone, calnexin, presumably through enhancing chaperone activity. Because calnexin is ubiquitously and constitutively expressed but EBI3 expression is inducible, these results could open an avenue to establish a new paradigm in which EBI3 plays an important role in further increasing the expression of target molecules at the protein level in collaboration with calnexin under inflammatory conditions. This theory well accounts for the heterodimer formation of EBI3 with p28, and probably with p35 and p19 to produce IL-27, IL-35, and IL-39, respectively. In line with this concept, another β-subunit, p40, plays a critical role in the assembly-induced proper folding of p35 and p19 to produce IL-12 and IL-23, respectively. Thus, chaperone-like activities in proper folding and maturation, which allow the secretion of biologically active heterodimeric cytokines, have recently been highlighted. This review summarizes the current understanding of chaperone-like activities of EBI3 to form heterodimers and other associations together with their possible biological implications.

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IL-30† (IL-27A): a familiar stranger in immunity, inflammation, and cancer

Cited by 18 publications

References 104 publications

Interleukin-30 Suppresses Not Only CD4+ T Cells but Also Regulatory T Cells in Murine Primary Biliary Cholangitis

Interleukin-30 Suppresses Not Only CD4+ T Cells but Also Regulatory T Cells in Murine Primary Biliary Cholangitis

Structural basis of activation and antagonism of receptor signaling mediated by interleukin-27

A Chaperone-Like Role for EBI3 in Collaboration With Calnexin Under Inflammatory Conditions

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