that alveolar macrophages are poised to respond to IL-36 cytokines in the lung. While we speculate that the responses of lung CD11c+ cells to IL-36a would be largely similar to the responses reported in the current study, further studies are required to determine the functional effects of IL-36a on lung specific CD11c+ cells and subsets. IL-36a activated NF-kB in mouse macrophages. Activation of NF-kB in the lungs leads to airway inflammation, mucus cell metaplasia and the production of proinflammatory cytokine and chemokines [66–68]. Agonist members of the novel IL-1 cytokine cluster induced NF-kB and MAPK activation in Jurkat cells transfected with IL-36R [31]. We previously demonstrated that IL-36c induced NF-kB activation in mouse macrophages following in vitro stimulation and in total lung tissue following a single intratracheal challenge with IL-36c [38]. In addition, IL-36c also induced NF-kB activation in lung fibroblasts [39]. Consistent with these findings, IL-36a also induced NF-kB activation in mouse macrophages, which may be a potential mechanism driving the production of neutrophil-specific che- mokines from macrophages and dendritic cells in the lung resulting in recruitment of neutrophils. Furthermore, these results also confirm previous findings that NF-kB is a critical signaling molecule downstream of both IL-1R1 and IL-36R mediated responses. To date, the role of IL-36a has not been examined in human inflammatory lung disease. It is interesting that very high concentrations of the IL-36 agonists including IL-36a are required to stimulate in vitro cellular responses [30,31]. A recent report demonstrates that truncation variants of IL-36a, IL-36b and IL-36c exert enhanced agonist activity in vitro, suggesting that a yet unidentified protease may process these cytokines to more biologically potent forms in vivo [69]. 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