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

Abstract

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.

TAK-242 ameliorates contact dermatitis exacerbated by IL-36 receptor antagonist deficiency

“…In fact, it has been reported that IL-17A regulates epidermal keratinocytes to produce chemokines such as CXCL1 and CXCL2 to induce neutrophils. In addition, it has also been reported that IL-39, which is a hetero dimer of IL-23p19 and EBI3, is downstream of IL-36γ and involved in the induction of neutrophils 30 . When IL-36Ra is lost, neutrophil-induced pathways, triggered by increased chemokines and IL-39, are further amplified through a positive feedback loop, which is consistent with the increase in neutrophils which we observed in our histopathological investigations.…”

Regulation of the Peptidoglycan Amidase PGLYRP2 in Epithelial Cells by Interleukin-36γ

“…IL-36 cytokines are important regulators of mucosal homeostasis and inflammation. We recently established that oral epithelial cells selectively upregulate IL-36␥ in response to the bacterial pathogen P. gingivalis (24) and that IL-36␥ can stimulate oral epithelial cells to express inflammatory cytokines (24,26). Here, we have established that IL-36␥ also regulates the expression of antimicrobial proteins by oral epithelial cells, including the peptidoglycan amidase PGLYRP2.…”

“…Antimicrobial proteins and cytokines are important mediators of mucosal homeostasis and inflammation. We have previously shown that IL-36␥ regulates the expression of various inflammatory cytokines in oral epithelial cells (24,26). Thus, we sought to establish whether it also regulates the expression of antimicrobial proteins.…”

“…3B). In addition to IRAK1, IL-36␥ activates the mitogen-activated protein (MAP) kinases p38 MAP kinase and ERK1/2 and the NF-B transcription factor in TIGK cells (26). Thus, we used pharmacologic inhibitors to establish their importance for the stimulation of PGLYRP2 by IL-36␥.…”

“…The expression of IL-36 cytokines by different cell types, including epithelial cells, has been shown to be induced by TLR signaling (23,24). IL-36 cytokines can induce inflammation by stimulating the expression of cytokines and chemokines by epithelial cells and innate immune cells (e.g., dendritic cells) (17)(18)(19)(20)(21)(22)(23)(24)(25)(26). IL-36 cytokines have also been shown to regulate T-helper cells (20,25).…”