IL-36γ signaling controls the induced regulatory T cell–Th9 cell balance via NFκB activation and STAT transcription factors

Harusato, Akihito; Abo, Hirohito; Ngo, Vu L.; Yi, Samuel Won-zu; Mitsutake, Kazunori; Osuka, Satoru; Kohlmeier, Jacob E.; Li, Jian Dong; Gewirtz, Andrew T.; Nusrat, Asma; Denning, Timothy L.

doi:10.1038/mi.2017.21

Cited by 85 publications

(109 citation statements)

References 50 publications

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“…These concentrations are consistent with prior reports in the literature studying IL-36γ in the lung, skin, and intestines [25, 38–41]. Aggregates were treated with acyclovir (ACV; GlaxoSmithKline, Research Triangle Park, NC) at 20 μg/ml as a positive control, or left untreated as a negative control.…”

Section: Methodssupporting

confidence: 86%

IL-36γ induces a transient HSV-2 resistant environment that protects against genital disease and pathogenesis

Gardner

Herbst-Kralovetz

2018

Cytokine

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Herpes simplex virus 2 (HSV-2) causes a persistent, lifelong infection that increases risk for sexually transmitted infection acquisition. Both the lack of a vaccine and the need for chronic suppressive therapies to control infection presents the need to further understand immune mechanisms in response to acute HSV-2 infection. The IL-36 cytokines are recently identified members of the IL-1 family and function as inflammatory mediators at epithelial sites. Here, we first used a well-characterized three-dimensional (3-D) human vaginal epithelial cell (VEC) model to understand the role of IL-36γ in the context of HSV-2 infection. In 3-D VEC, IL-36γ is induced by HSV-2 infection, and pretreatment with exogenous IL-36γ significantly reduced HSV-2 replication. To assess the impact of IL-36γ treatment on HSV-2 disease pathogenesis, we employed a lethal genital infection model. We showed that IL-36γ treatment in mice prior to lethal intravaginal challenge significantly limited vaginal viral replication, delayed disease onset, decreased disease severity, and significantly increased survival. We demonstrated that IL-36γ treatment transiently induced pro-inflammatory cytokines, chemokines, and antimicrobial peptides in murine lower female reproductive tract (FRT) tissue and vaginal lavages. Induction of the chemokines CCL20 and KC in IL-36γ treated mice also corresponded with increased polymorphonuclear (PMN) leukocyte infiltration observed in vaginal smears. Altogether, these studies demonstrate that IL-36γ drives the transient production of immune mediators and promotes PMN recruitment in the vaginal microenvironment that increases resistance to HSV-2 infection and disease. Our data indicate that IL-36γ may participate as a key player in host defense mechanisms against invading pathogens in the FRT.

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Section: Methodssupporting

confidence: 86%

IL-36γ induces a transient HSV-2 resistant environment that protects against genital disease and pathogenesis

Gardner

Herbst-Kralovetz

2018

Cytokine

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“…IL‐36 cytokines are important regulators of mucosal homeostasis and inflammation . In this study, we discovered that IL‐36γ stimulates oral epithelial cells to selectively express the IL‐12 cytokine family members, IL‐23p19 and EBI3 .…”

Section: Discussionmentioning

confidence: 89%

“…IL‐36 family cytokines (IL‐36α, IL‐36β and IL‐36γ), which belong to the IL‐1 super‐family, have recently emerged as key regulators of immune responses at mucosal sites . They are expressed by a range of cell types, including mucosal epithelial cells, macrophages and dendritic cells, and induced in response to TLR signaling .…”

Section: Introductionmentioning

confidence: 99%

“…They are expressed by a range of cell types, including mucosal epithelial cells, macrophages and dendritic cells, and induced in response to TLR signaling . IL‐36 cytokines are potent stimulators of the expression of neutrophil chemokines, such as IL‐8 and chemokine (C‐X‐C motif) ligand 1 ( CXCL1 ), by mucosal epithelial cells and innate immune cells, and accordingly are important regulators of neutrophil responses during infection . IL‐36 cytokines can also regulate immune responses by stimulating the expression of T‐cell chemokines, including CXCL10 and chemokine (C‐C motif) ligand 20 ( CCL20 ) .…”

Section: Introductionmentioning

confidence: 99%

“…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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Current perspectives on the interleukin‐1 family as targets for inflammatory disease

et al. 2019

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Since the first description of interleukin-1 (IL-1) and the genesis of the field of cytokine biology, the understanding of how IL-1 and related cytokines play central orchestrating roles in the inflammatory response has been an area of intense investigation. As a consequence of these endeavours, specific strategies have been developed to target the function of the IL-1 family in human disease realizing significant impacts for patients. While the most significant advances to date have been associated with inhibition of the prototypical family members IL-1α/β, approaches to target more recently identified family members such as IL-18, IL-33 and the IL-36 subfamily are now beginning to come to fruition. This review summarizes current knowledge surrounding the roles of the IL-1 family in human disease and describes the rationale and strategies which have been developed to target these cytokines to inhibit the pathogenesis of a wide range of diseases in which inflammation plays a centrally important role.Keywords: Canakinumab r Inflammation r Inflammatory disease r Interleukin-1 family r Therapy

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IL-36γ signaling controls the induced regulatory T cell–Th9 cell balance via NFκB activation and STAT transcription factors

Cited by 85 publications

References 50 publications

IL-36γ induces a transient HSV-2 resistant environment that protects against genital disease and pathogenesis

IL-36γ induces a transient HSV-2 resistant environment that protects against genital disease and pathogenesis

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

Current perspectives on the interleukin‐1 family as targets for inflammatory disease

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