Characterization of IL-18 Expression and Release in the Pathogenesis of Chronic Rhinosinusitis

Abstract

Background: Interleukin-18 (IL-18) is a member of the IL-1 cytokine family that affects chronic inflammation. We sought to characterize IL-18 expression and investigate its release during chronic rhinosinusitis (CRS). Methods: The expression of IL-18 in nasal polyps (NPs) and uncinate tissues (UTs) from both CRS and non-CRS patients was examined via immunohistochemistry. After culturing dispersed NP cells (DNPCs) with or without various stimulations, IL-18 levels were measured in the culture supernatants. Furthermore, the effect of IL-18 neutralization on staphylococcus enterotoxin B (SEB)-induced cytokine production was also examined. Results: Similar expression of IL-18 in the epithelial layers was observed between the NPs and UTs. However, there was a significantly higher number of IL-18⁺ cells in the lamina propria from NPs compared to UTs without CRS. This increased number was significantly correlated with the radiological severity of sinusitis and local eosinophilia. After the dispersion, IL-18 was spontaneously released by NP cells in a phase-dependent manner. While SEB, fungal antigens, and TLR agonists did not enhance the release, exposure to protease or one cycle of a freeze-and-thaw treatment did induce release of IL-18 from rested DNPCs. In addition, neutralization of IL-18 significantly suppressed SEB-induced IL-5, IL-13, and IFN-γ, but not IL-17A production. Conclusions: These results suggest that the pro-inflammatory effect of IL-18 released by danger signals may be involved in the pathogenesis of CRS, which includes eosinophilic inflammation and NP formation, via the augmentation of both Th2- and Th1-associated cytokine production.

Group 2 innate lymphoid cells in nasal polyposis

“…28,29 In contrast, elevations in IL-1b and IL-18 are reported in Asian NPs. 30,31 Figure 2. Potential roles for ILC2s in driving CRSwNP pathogenesis.…”

Inhibiting the type 2 inflammatory pathway with dupilumab is associated with an increase in interleukin‐4 and interleukin‐18 production

“…We also observed increased secretion of cytokine IL‐18 ( p = 0.042) and a trend toward increased CXCL8/IL‐8 ( p = 0.126). IL‐18 is a pleiotropic cytokine shown to modulate both type 1 and type 2 inflammation in CRS 7 . IL‐18 in synergy with IL‐12 is a potent inducer of a Th1 cell response, characterized by IFN‐γ production 7 .…”

Regulation of Nasal Airway Homeostasis and Inflammation in Mice by SHP-1 and Th2/Th1 Signaling Pathways

“…IL-18 is up-regulated in the nasal secretions from patients with allergic rhinitis [35] or with flour allergen change [36]. It is produced by dispersed nasal polyp cells from AR patients [37], probably through promoting Th2 cytokine production. Interestingly, clinical improvement in allergic rhinitis patients with allergen specific immunotherapy (SIT) was associated with increased IL-18 in the serum or by PBMC [38]–[40].…”