IL-36 Cytokines Promote Inflammation in the Lungs of Long-Term Smokers

Abstract

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease with high morbidity and mortality. The IL-36 family are proinflammatory cytokines that are known to shape innate immune responses, including those critical to bacterial pneumonia. The objective of this study was to determine whether IL-36 cytokines promote a proinflammatory milieu in the lungs of long-term smokers with and without COPD. Concentrations of IL-36 cytokines were measured in plasma and BAL fluid from subjects in a pilot study (<i>n</i> = 23) of long-term smokers with and without COPD <i>in vivo</i> and from a variety of lung cells (from 3-5 donors) stimulated with bacteria or cigarette smoke components <i>in vitro</i>. Pulmonary macrophages were stimulated with IL-36 cytokines <i>in vitro</i>, and chemokine and cytokine production was assessed. IL-36α and IL-36γ are produced to varying degrees in murine and human lung cells in response to bacterial stimuli and cigarette smoke components <i>in vitro</i>. Moreover, whereas IL-36γ production is upregulated early after cigarette smoke stimulation and wanes over time, IL-36α production requires a longer duration of exposure. IL-36α and IL-36γ are enhanced systemically and locally in long-term smokers with and without COPD, and local IL-36α concentrations display a positive correlation with declining ventilatory lung function and increasing proinflammatory cytokine concentrations. <i>In vitro</i>, IL-36α and IL-36γ induce proinflammatory chemokines and cytokines in a concentration-dependent fashion that requires IL-36R and MyD88. IL-36 cytokine production is altered in long-term smokers with and without COPD and contributes to shaping a proinflammatory milieu in the lungs.