Influence of serum IL-36 subfamily cytokines on clinical manifestations of asthma

Abstract

Background: The IL-36 subfamily, a member of the IL-1 superfamily, is thought to promote type 2 (T2) and non-T2 inflammation and involved in autoimmune and airway disease progression. However, its role in asthma remains unclear.

Objective: We sought to determine the contribution of the IL-36 subfamily to the clinical manifestation of asthma.

Methods: The levels of serum IL-36α, IL-36β, and IL-36γ, recognized as IL-36 subfamily agonists, and IL-36 receptor antagonist (IL-36Ra) and IL-38, recognized as IL-36 subfamily antagonists, were measured by ELISA in 110 asthma patients (55 with nonsevere and 55 with severe asthma) aged ≥20 years and 31 healthy individuals. The association of IL-36 with clinical indices and inflammatory mediators was examined. The characteristics of high and low IL-36 subgroups were explored.

Results: IL-36α, IL-36γ, and IL-36Ra levels were significantly higher in asthma patients, especially patients with severe asthma, than in healthy controls. The high IL-36γ group exhibited lower Asthma Control Test scores (P = .01), more frequent asthma exacerbations (AEs), and higher hazard ratio for AEs. The high IL-36Ra group exhibited higher values of forced expiratory volume in 1 second, more frequent severe AEs, and higher hazard ratio for severe exacerbations. The IL-36 cytokine levels, except for IL 36α, were positively correlated with IL-6, IL-13, IL-17, and/or IFN-γ levels. IL-36Ra was positively correlated with age-adjusted forced expiratory volume and forced vital capacity.

Conclusion: A systemically high IL-36 level is associated with asthma severity and with both T2 and non-T2 cytokines, and it implies poor condition and enhancement of risk of AEs in asthma patients.

Keywords: Asthma; IL-36; IL-6; acute exacerbation; non–type 2; pulmonary function; type 2.

Fig 1

Serum IL-36 subfamily cytokines of patients with nonsevere and severe asthma and healthy controls. Median (interquartile range) (pg/mL) in 31 healthy controls, 55 patients with nonsevere asthma, and 55 patients with severe asthma, respectively, for: (A) serum IL-36α: 12.5 (12.5-12.5), 18.3 (12.5-57.4), 12.5 (12.5-12.5), respectively; (B) serum IL-36β: 12.5 (12.5-229.0), 12.5 (12.5-365.9), 12.5 (12.5-132.7), (C) serum IL-36γ: 18.8 (18.8-362.2), 18.8 (18.8-270.8), 18.8 (18.8-18.8), (D) serum IL-36Ra: 93.8 (93.8-93.8), 93.8 (93.8-93.8), 93.8 (93.8-93.8), and (E) serum IL-38: 31.2 (31.2-54.1), 31.2 (31.2-183.1), 31.2 (31.2-34.5). Values are log transformed for statistical analysis by Mann-Whitney U test and Kruskal-Wallis tests. Healthy indicates healthy control participants; nonsevere, patients with nonsevere asthma; and severe, patients with severe asthma.

Fig 2

Ratio of patients experiencing AE and time to first AE in 6 months. Comparison of (A) ratio of patients having AE and (B) free time to first AE between high and low serum IL-36γ subgroups. Comparison of (C) ratio of patients with SAE and (D) time to first SAE between high and low serum IL-36Ra subgroups.

Fig 3

Relationships between serum IL-36Ra and pulmonary function in patients with asthma. Relationships between serum IL-36Ra and (A) FEV₁ (r = 0.21, P = .02) or (B) FVC (r = 0.21, P = .02) in asthma patients, adjusted by age as covariance. Statistical significance was determined by Spearman correlation test and partial correlation analysis.

Fig 4

Correlations of serum IL-36 subfamily cytokine and serum cytokines in patients with asthma. Correlation of (A) IL-36α with IFN-γ (r = 0.34, P < .0001); IL-36β with IL-6 (r = 0.20, P = .045), IL-13 (r = 0.26, P = .008), and IL-17 (r = 0.72, P < .0001); (B) IL-36γ with IL-13 (r = 0.22, P = .023) and IL-17 (r = 0.29, P = .003); (C) IL-36Ra with IL-6 (r = 0.27, P = .005), IL-13 (r = 0.23, P = .019), IL-17 (r = 0.42, P < .0001), and IFN-γ (r = 0.34, P = .016); and (D) IL-38 with IL-6 (r = 0.24, P = .014), IL-13 (r = 0.35, P < .0001), and IL-17 (r = 0.69, P < .0001). Statistical significance was determined by Spearman and partial correlation analysis.

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