Human IL-35 Inhibits the Bioactivity of IL-12 and Its Interaction with IL-12Rβ2

Mahfooz, Najmus; Merling, Marlena R; Claeys, Tiffany A.; Dowling, Jack W; Forero, Adriana; Robinson, Richard

doi:10.4049/immunohorizons.2300039

Cited by 6 publications

(3 citation statements)

References 60 publications

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“…This may be reconciled by considering the signaling capabilities of IL-12 family α subunits at higher concentrations ( 43 , 59 ), masking inhibitory effects. IL-12 inhibition has also recently been reported for IL-35 ( 60 ). Here, commercial IL-35 was used that may also contain IL-12α.…”

Section: Discussionmentioning

confidence: 66%

Human interleukin-12α and EBI3 are cytokines with anti-inflammatory functions

Hildenbrand,

Bohnacker,

Menon

et al. 2023

Sci. Adv.

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Interleukins are secreted proteins that regulate immune responses. Among these, the interleukin 12 (IL-12) family holds a central position in inflammatory and infectious diseases. Each family member consists of an α and a β subunit that together form a composite cytokine. Within the IL-12 family, IL-35 remains particularly ill-characterized on a molecular level despite its key role in autoimmune diseases and cancer. Here we show that both IL-35 subunits, IL-12α and EBI3, mutually promote their secretion from cells but are not necessarily secreted as a heterodimer. Our data demonstrate that IL-12α and EBI3 are stable proteins in isolation that act as anti-inflammatory molecules. Both reduce secretion of proinflammatory cytokines and induce the development of regulatory T cells. Together, our study reveals IL-12α and EBI3, the subunits of IL-35, to be functionally active anti-inflammatory immune molecules on their own. This extends our understanding of the human cytokine repertoire as a basis for immunotherapeutic approaches.

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Section: Discussionmentioning

confidence: 66%

Human interleukin-12α and EBI3 are cytokines with anti-inflammatory functions

Hildenbrand,

Bohnacker,

Menon

et al. 2023

Sci. Adv.

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“…Our data indicate for the first time that short-term exposure of NK cells to IL-35 weakens their activation and production of proinflammatory cytokines/chemokines in response to IL-2, IL-12, IL-18, and IL-15. Because IL-35 and IL-12 share the p35 subunit, it has been recently described that IL-35 inhibits IL-12 stimulation by competing with the IL-12Rβ2 receptor 48 . However, this mechanism cannot be applied to IL-2, IL-15, and IL-18, suggesting that IL-35 by itself mediates inhibitory signaling cascades in human NK cells.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-35 impairs human NK cell effector functions and induces their ILC1-like conversion with tissue residency features

Bendriss-Vermare,

Picant,

Revol-Bauz

et al. 2024

Preprint

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Natural Killer (NK) cells lose their effector functions towards dangerous cells in chronic inflammatory diseases through still elusive mechanisms. Here, we demonstrate that Interleukin 35 (IL-35), an immunosuppressive member of the IL-12 family, inhibits human NK cell proliferation, pro-inflammatory, and cytotoxic functions, while promoting their secretion of TGF-β and proangiogenic factors. Furthermore, prolonged exposure to IL-35 converts NK cells into ILC1-like cells with tissue residency features (CD9+CD103+CD49a+) and low effector functions, that was dependent on autocrine TGF-β. Single cell RNAseq analysis also revealed an ILC1-like heterogeneity associated to the initial NK subpopulation, conventional or adaptive, undergoing the conversion. Overall, our findings identify a new role of IL-35 as a key driver of NK cell plasticity leading to the acquisition of tissue residency features and weakened effector functions that might play a role in physiopathological contexts and represent an attractive target for future immunotherapies to improve NK cell clinical activity.

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“…Differences in phenotypes associated with mutation in IL11RA or IL11 are often suggested to be due to ‘ unknown extra ligands ’ that bind to IL11RA. While this is possible, it is equally likely, and supported by experimental findings in related contexts, that loss of IL11RA increases gp130 availability for other gp130 binding ligands/receptors that results in additional phenotypes [ 62 , 141 , 142 ].…”

Section: Human and Mouse Genetics Of Il11 And Il11ramentioning

confidence: 99%

Understanding interleukin 11 as a disease gene and therapeutic target

Cook

2023

Biochemical Journal

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Interleukin 11 (IL11) is an elusive member of the IL6 family of cytokines. While initially thought to be a haematopoietic and cytoprotective factor, more recent data show instead that IL11 is redundant for haematopoiesis and toxic. In this review, the reasons that led to the original misunderstandings of IL11 biology, which are now understandable, are explained with particular attention on the use of recombinant human IL11 in mice and humans. Following tissue injury, as part of an evolutionary ancient homeostatic response, IL11 is secreted from damaged mammalian cells to signal via JAK/STAT3, ERK/P90RSK, LKB1/mTOR and GSK3β/SNAI1 in autocrine and paracrine. This activates a program of mesenchymal transition of epithelial, stromal, and endothelial cells to cause inflammation, fibrosis, and stalled endogenous tissue repair, leading to organ failure. The role of IL11 signalling in cell- and organ-specific pathobiology is described, the large unknowns about IL11 biology are discussed and the promise of targeting IL11 signalling as a therapeutic approach is reviewed.

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Human IL-35 Inhibits the Bioactivity of IL-12 and Its Interaction with IL-12Rβ2

Cited by 6 publications

References 60 publications

Human interleukin-12α and EBI3 are cytokines with anti-inflammatory functions

Human interleukin-12α and EBI3 are cytokines with anti-inflammatory functions

Interleukin-35 impairs human NK cell effector functions and induces their ILC1-like conversion with tissue residency features

Understanding interleukin 11 as a disease gene and therapeutic target

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