Interleukin-30 (IL27p28) alleviates experimental sepsis by modulating cytokine profile in NKT cells

Yan, Jun; Mitra, Abhisek; Hu, Jiemiao; Cutrera, Jeffery J.; Xia, Xueqing; Doetschman, Thomas; Gagea, Mihai; Mishra, Lopa; Li, Shulin

doi:10.1016/j.jhep.2015.12.020

Cited by 32 publications

(36 citation statements)

References 31 publications

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“…A Single Amino Acid Switch Regulates IL-27α Secretion. The difference in secretion between human and murine IL-27α warrants further investigation, since murine IL-27α has immunomodulatory functions (13)(14)(15)(16) and exerts protective roles in sepsis, graftversus-host disease, liver fibrosis, and autoimmunity (15,17,25,26). These functions will be absent in the human system due to the lack of hIL-27α secretion.…”

Section: Resultsmentioning

confidence: 99%

“…The hIL-27α L162C mutant provided us with secretion-competent human IL-27α. For the corresponding mouse cytokine, it is still debated if it performs agonistic or antagonistic roles (13)(14)(15)(16)(17). To assess the biological effects of hIL-27α L162C , we produced the protein in mammalian cells (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We find IL-27α L162C to modulate the production of multiple cytokines by human monocytic cells, including neutrophil chemoattractants (CXCL-1 and CXCL-10) and antiinflammatory IL-10. This is of particular relevance since these mediators may contribute to the protective roles of IL-27α in murine models of sepsis (17,44,45) or graft-versus-host disease (46). No good treatment options are currently available for these conditions in human patients.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, no autonomous secretion of human IL-27α has been reported yet. The molecular basis for this difference has remained unclear, but it is likely to have a profound impact on immune system function, since in mice IL-27 and its α-subunit both strongly influence inflammatory diseases (4,17), where significant differences between mouse and man exist (18).…”

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confidence: 99%

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A folding switch regulates interleukin 27 biogenesis and secretion of its α-subunit as a cytokine

Müller

Friedl

Aschenbrenner

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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A common design principle of heteromeric signaling proteins is the use of shared subunits. This allows encoding of complex messages while maintaining evolutionary flexibility. How cells regulate and control assembly of such composite signaling proteins remains an important open question. An example of particular complexity and biological relevance is the interleukin 12 (IL-12) family. Four functionally distinct αβ heterodimers are assembled from only five subunits to regulate immune cell function and development. In addition, some subunits act as independent signaling molecules. Here we unveil key molecular mechanisms governing IL-27 biogenesis, an IL-12 family member that limits infections and autoimmunity. In mice, the IL-27α subunit is secreted as a cytokine, whereas in humans only heterodimeric IL-27 is present. Surprisingly, we find that differences in a single amino acid determine if IL-27α can be secreted autonomously, acting as a signaling molecule, or if it depends on heterodimerization for secretion. By combining computer simulations with biochemical experiments, we dissect the underlying structural determinants: a protein folding switch coupled to disulfide bond formation regulates chaperone-mediated retention versus secretion. Using these insights, we rationally change folding and assembly control for this protein. This provides the basis for a more human-like IL-27 system in mice and establishes a secretion-competent human IL-27α that signals on its own and can regulate immune cell function. Taken together, our data reveal a close link between protein folding and immunoregulation. Insights into the underlying mechanisms can be used to engineer immune modulators.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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A folding switch regulates interleukin 27 biogenesis and secretion of its α-subunit as a cytokine

Müller

Friedl

Aschenbrenner

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…p40 also binds to p28 to form p28/p40, tentatively called IL-Y, but this complex was demonstrated to be an antagonist to the signaling by IL-12 and IL-27 (15, 16). In addition, biological activities of monomeric forms of p28 (17), EBI3 (18), and p19 (19) and generation of soluble receptors of WSX-1 (20) and IL-23R (21) as antagonists to IL-27 and IL-23, respectively, were reported as well.…”

Section: Introductionmentioning

confidence: 99%

Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

et al. 2016

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The interleukin (IL)-6/IL-12 family cytokines have pleiotropic functions and play critical roles in multiple immune responses. This cytokine family has very unique characteristics in that they comprise two distinct subunits forming a heterodimer and each cytokine and receptor subunit shares with each other. The members of this cytokine family are increasing; currently, there are more than six cytokines, including the tentatively named cytokines IL-Y (p28/p40), IL-12 (p35/p40), IL-23 (p19/p40), IL-27 [p28/Epstein–Barr virus-induced protein 3 (EBI3)], IL-35 (p35/EBI3), and IL-39 (p19/EBI3). This family of cytokines covers a very broad range of immune responses, including pro-inflammatory responses, such as helper T (Th)1, Th2, and Th17, to anti-inflammatory responses, such as regulatory T (Treg) cells and IL-10-producing Treg cells. IL-12 is the first member of this family, and IL-12, IL-23, and IL-27 are mainly produced by activated antigen-presenting cells, such as dendritic cells and macrophages. IL-12 plays a critical role in the promotion of Th1 immune responses by inducing interferon-γ production to combat pathogens and malignant tumors. IL-23 induces IL-17 production and is necessary to maintain pathogenic Th17 cells that cause inflammatory and autoimmune diseases. IL-27 was initially reported to play a critical role in promotion of Th1 differentiation; however, subsequent studies revealed that IL-27 has broader stimulatory and inhibitory roles by inducing IL-10-producing Treg cells. IL-35 is produced by forkhead box P3+ Treg cells and activated B cells and has immunosuppressive functions to maintain immune tolerance. The most recently identified cytokine, IL-39, is produced by activated B cells and has pro-inflammatory functions. The cytokine tentatively named IL-Y seems to have anti-inflammatory functions by inhibiting Th1 and Th17 differentiation. In addition, individual cytokine subunits were also shown to have self-standing activities. Thus, promiscuity within the IL-6/IL-12 family cytokines complicates structural and functional clarification and assignment of individual cytokines. A better understanding of the recent advances and expanding diversity in molecular structures and functions of the IL-6/IL-12 family cytokines could allow the creation of novel therapeutic strategies by using them as tools and targeted molecules.

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Human neutrophils activated by TLR8 agonists, with or without IFNγ, synthesize and release EBI3, but not IL-12, IL-27, IL-35, or IL-39

Cassatella

Gardiman

Arruda‐Silva

et al. 2020

Journal of Leukocyte Biology

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The IL-12 family of cytokines plays crucial functions in innate and adaptive immunity. These cytokines include heterodimers sharing distinct (IL-12A, IL-23A, and IL-27A) with two (IL-12B and Epstein-Barr virus induced gene 3 [EBI3]) chains, respectively, IL-12 (IL-12B plus IL-12A) and IL-23 (IL-12B plus IL-23A) sharing IL-12B, IL-27 (EBI3 plus IL-27A), IL-35 (EBI3 plus IL-12A), and IL-39 (EBI3 plus IL-23A) sharing EBI3. In this context, we have recently reported that highly pure neutrophils incubated with TLR8 agonists produce functional IL-23. Previously, we showed that neutrophils incubated with LPS plus IFN for 20 h produce IL-12. Herein, we investigated whether highly pure, TLR8-activated, neutrophils produce EBI3, and in turn IL-27, IL-35, and IL-39, the IL-12 members containing it. We report that neutrophils incubated with TLR8 ligands, TNF and, to a lesser extent, LPS, produce and release remarkable amounts of EBI3, but not IL-27A, consequently excluding the possibility for an IL-27 production. We also report a series of unsuccessful experiments performed to investigate whether neutrophil-derived EBI3 associates with IL-23A to form IL-39. Furthermore, we show that neutrophils incubated with IFN in combination with either TLR8 or TLR4 ligands express/produce neither IL-12, nor IL-35, due to the inability of IFN , contrary to previous findings, to activate IL12A transcription. Even IL-27 was undetectable in supernatants harvested from IFN plus R848-treated neutrophils, although they were found to accumulate IL27A transcripts. Finally, by immunohistochemistry experiments, EBI3-positive neutrophils were found in discrete pathologies only, including diverticulitis, cholecystitis, Gorham disease, and Bartonella Henselae infection, implying a specific role of neutrophil-derived EBI3 in vivo.

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Interleukin-30 (IL27p28) alleviates experimental sepsis by modulating cytokine profile in NKT cells

Cited by 32 publications

References 31 publications

A folding switch regulates interleukin 27 biogenesis and secretion of its α-subunit as a cytokine

A folding switch regulates interleukin 27 biogenesis and secretion of its α-subunit as a cytokine

Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

Human neutrophils activated by TLR8 agonists, with or without IFNγ, synthesize and release EBI3, but not IL-12, IL-27, IL-35, or IL-39

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