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

• Published in: Immunology and cell biology Vol. 96; no. 6; pp. 646 - 655
• Main Authors: Scholz, Glen M, Heath, Jacqueline E, Walsh, Katrina A, Reynolds, Eric C
• Format: Journal Article
• Language: English
• Published: United States Blackwell Science Ltd 01.07.2018
• Subjects: Autocrine signalling; Cytokines; EBI3; EGF; Epidermal growth factor; Epidermal growth factor receptors; Epithelial cells; Epithelium; Epstein-Barr virus; ERK1/2; Extracellular signal-regulated kinase; Homeostasis; IL‐36; IL‐39; Interleukin 12; Interleukin 6; MAP kinase; Mucosa; Protein expression; Protein kinase; epithelial cells; ERK1/2; IL-36; EGF; EBI3; IL-39
• ISSN: 0818-9641; 1440-1711
• DOI: 10.1111/imcb.12029

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. IL‐36γ stimulation of human oral epithelial cells induced the expression of IL‐23p19 and EBI3, the subunits of the novel IL‐12 family cytokine IL‐39. Notably, their IL‐36γ‐inducible expression was not only diametrically regulated by MEK‐ERK signaling, but also modulated, in a MEK‐ERK dependent manner, by EGF receptor signaling. Thus, this study provides important new insight into how IL‐36γ may control mucosal inflammation.