Cigarette smoke (CS) is the principal cause of pulmonary inflammatory response. IL-28 (IFN-lambda) is a novel group of class II cytokines targeting the epithelial cells and IL-28 responses prominent in lungs can exert important immunomodulatory effects. We tested the hypothesis that IL-28B may modulate the lung inflammation induced by CS. Groups of mice were exposed to CS two times per day for 11 consecutive days. CS exposure induced lymphocyte, neutrophil and macrophage infiltration and inflammatory cytokine (IL-1 beta, tumor necrosis factor-alpha (TNF)-alpha, IL-17, and IL-4) in the airways. More importantly, all these CS-induced pathogenic changes were significantly inhibited by hydrodynamic delivery of plasmid DNA encoding mouse IL-28B. Thus, our results suggest that IL-28 cytokines are beneficial for the suppression of CS-mediated airway inflammation and may be a therapeutic target in CS-related diseases. (C) 2014 Elsevier Inc. All rights reserved.