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IL-32, a Novel Proinflammatory Cytokine in Chronic Obstructive Pulmonary Disease

¹ Department of Medical Diagnostic Sciences and Special Therapies, University of Padova; ² Department of Cardiac, Thoracic, and Vascular Sciences, University of Padova and Padova City Hospital; and ³ Department of Environmental Medicine and Public Health, University of Padova, Padova, Italy; ⁴ Department of Clinical and Experimental Medicine, University of Ferrara, Ferrara, Italy; ⁵ Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy; and ⁶ University of Colorado Health Sciences Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Marina Saetta, M.D., Università degli Studi di Padova, Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari, Unità Operativa di Pneumologia, Via Giustiniani 3, 35128 Padova, Italy. E-mail: marina.saetta{at}unipd.it

Rationale: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder of the lung, yet the mechanisms that regulate this immune-inflammatory response are not fully understood.

Objectives: We investigated whether IL-32, a newly discovered cytokine, was related to markers of inflammation and clinical progression in COPD.

Methods: Using immunohistochemistry, expression of IL-32 was examined in surgically resected specimens from 40 smokers with COPD (FEV₁ = 39 ± 4% predicted), 11 smokers with normal lung function, and 9 nonsmoking control subjects. IL-32 was quantified in alveolar macrophages, alveolar walls, bronchioles, and arterioles, and confirmed by molecular analysis. The levels of IL-32 were correlated with the cellular infiltrates, markers of inflammation, and clinical data.

Measurements and Main Results: Macrophage staining for IL-32 was increased in smokers with COPD compared with control smokers and nonsmokers (P = 0.0014 and P < 0.0001, respectively), and similar differences were observed in alveolar walls (P = 0.0004 and P = 0.0005) and bronchiolar epithelium (P = 0.004 and P = 0.0009). This increase was also detected at the mRNA level (P = 0.007 vs. control smokers and P = 0.029 vs. nonsmokers) and was mainly due to non- isoforms. Moreover, IL-32 expression was positively correlated with tumor necrosis factor- (P = 0.004, r_s=0.70), CD8⁺cells (P = 0.02, r_s=0.46), phospho p38MAPK (P < 0.01, r_s=0.60) and negatively with FEV₁ values (P = 0.004, r_s= –0.53).

Conclusions: This is the first study to demonstrate increased expression of IL-32 in lung tissue of patients with COPD, where it was colocalized with tumor necrosis factor- and correlated with the degree of airflow obstruction. These results suggest that IL-32 is implicated in the characteristic immune response of COPD, with a possible impact on disease progression.

Key Words: inflammatory cytokines • immune response • airflow limitation • cigarette smoking

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Chronic obstructive pulmonary disease (COPD) is characterized by an exaggerated immune response, but the mechanisms of this response are yet unknown. IL-32 has recently been proposed as a possible regulator of innate and adaptive responses, particularly in inflammatory diseases. What This Study Adds to the Field IL-32 protein and mRNA were increased in lungs of smokers with COPD compared with unaffected subjects. IL-32 correlated with tumor necrosis factor-, CD8+ cells, and phospho p38 mitogen-activated protein kinase, suggesting that this cytokine contributes to the characteristic immune response in COPD.

 

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