EBI3 Downregulation Contributes to Type I Collagen Overexpression in Scleroderma Skin

Kudo, Hideo; Wang, Zhongzhi; Jinnin, Masatoshi; Nakayama, Wakana; Inoue, Kuniko; Honda, Noritoshi; Nakashima, Taiken; Kajihara, Ikko; Makino, Katsunari; Makino, Takamitsu; Fukushima, Satoshi; Ihn, Hironobu

doi:10.4049/jimmunol.1402362

Cited by 26 publications

(24 citation statements)

References 42 publications

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“…IL‐23p19 was recently shown to heterodimerize with EBI3 to form IL‐39 . In addition, EBI3 can also function independently of IL‐23p19 (and IL‐12p35 and IL‐27p28) . Thus, the levels of IL‐23p19 and EBI3 in the cell culture supernatants were measured.…”

Section: Resultsmentioning

confidence: 99%

“…IL‐23p19 and EBI3 have recently been shown to form the novel cytokine IL‐39 and regulate neutrophil responses . EBI3 has been shown to also have IL‐12 cytokine‐independent functions . The selective stimulation of IL‐23p19 and EBI3 expression is therefore likely to play an important role in the control of mucosal immunity by IL‐36 cytokines.…”

Section: Discussionmentioning

confidence: 99%

“…Although a role for IL‐39 in the regulation of T cells has not been reported, it induces inflammation and promotes the expansion of neutrophils in lupus‐prone mice . EBI3 also has IL‐12 family cytokine‐independent functions, including mediating IL‐6 trans ‐signaling in CD4 + T cells, and inhibiting collagen expression in dermal fibroblasts . Significantly, IL‐36 cytokines can synergize with IL‐12 to promote the Th1 polarization of naïve T cells, and conversely inhibit the development of T regulatory cells …”

Section: Introductionmentioning

confidence: 99%

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MEK‐ERK signaling diametrically controls the stimulation of IL‐23p19 and EBI3 expression in epithelial cells by IL‐36γ

et al. 2018

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Interleukin (IL)-36 cytokines are important regulators of mucosal homeostasis and inflammation. We previously established that oral epithelial cells strongly upregulate IL-36γ expression in response to the bacterial pathogen Porphyromonas gingivalis. Here, we have established that IL-36γ stimulates the expression of the IL-12 cytokine family members, IL-23p19 and Epstein-Barr Virus-Induced Gene 3 (EBI3), by oral epithelial cells; their expression was also selectively stimulated by IL-36α. Notably, IL-23p19 and EBI3 expression was not stimulated by P. gingivalis, thus suggesting that their expression by the oral epithelium in response to P. gingivalis is likely to be mediated in an autocrine manner by IL-36γ. The IL-36γ-inducible expression of IL-23p19 and EBI3 was found to be diametrically regulated by the mitogen-activated protein kinase/extracellular signal regulated kinase (MEK)-extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, whereby the activation of MEK-ERK signaling likely functions as a negative feedback mechanism to limit EBI3 expression. Furthermore, epidermal growth factor receptor (EGFR) signaling, which is important for mucosal homeostasis, was demonstrated to modulate, in a MEK-ERK-dependent manner, the stimulation of IL-23p19 and EBI3 expression by IL-36γ. IL-23p19 and EBI3 have recently been shown to heterodimerize to form the novel cytokine IL-39 and promote neutrophil expansion. EBI3 has been shown to also have IL-12 cytokine family independent functions (e.g. mediating IL-6 trans-signaling). Thus, this study not only advances our understanding of how IL-36 cytokines may control mucosal inflammation, but also establishes EGFR signaling as a potentially important modulator of IL-36 cytokine function.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MEK‐ERK signaling diametrically controls the stimulation of IL‐23p19 and EBI3 expression in epithelial cells by IL‐36γ

et al. 2018

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“…Expression of EBI3, but not IL-35, was recently demonstrated to be decreased in the keratinocytes of the epidermis and Treg cells of the dermis in systemic sclerosis skin compared with normal skin, whereas injection of EBI3 alone into the skin improved mice skin fibrosis and addition of EBI3 alone in cultured dermal fibroblasts decreased type I collagen expression (18). Although the possibility that EBI3 may form a complex with endogenous p35 or other molecule cannot be excluded, EBI3 itself may directly affect collagen expression.…”

Section: Epstein–barr Virus-induced Proteinmentioning

confidence: 99%

“…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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EBI3 Downregulation Contributes to Type I Collagen Overexpression in Scleroderma Skin

Cited by 26 publications

References 42 publications

MEK‐ERK signaling diametrically controls the stimulation of IL‐23p19 and EBI3 expression in epithelial cells by IL‐36γ

MEK‐ERK signaling diametrically controls the stimulation of IL‐23p19 and EBI3 expression in epithelial cells by IL‐36γ

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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