Chronic Obstructive Pulmonary Diseases (COPD) such as bronchitis and lung emphysema are chronic airway diseases associated with inflammation and cigarette smoking. Airway epithelial cells are the first cells that will be exposed to cigarette smoke. In addition, epithelial cells are able to release the cytokines CXCL-8 and IL-1beta. These cytokines are involved in the acute and chronic character of inflammatory processes associated with COPD, respectively. The aim of this study was to investigate whether Toll Like Receptors (TLRs) in or on epithelial cells were involved in cigarette smoke-induced cytokine production. Here we demonstrate that cigarette smoke induces the release of CXCL-8, IL-1beta and IL-6 from human bronchial epithelial cells (HBE-14o cells). The cigarette smoke-induced CXCL-8 production was inhibited by an antibody against TLR4 and by inhibitory ODN without CpGODN motif suggesting the involvement of TLR4 and TLR9. In addition, exposure of HBE-14o cells to ligands specific for TLR4 (LPS) or TLR9 (CpGODN) resulted in the release of CXCL8 and IL1beta as well as IL-6. TLR4 and, interestingly, also TLR9 were present on the cell surface membrane of the HBE-14o cells. The surface expression of both receptors decreased after cigarette smoke exposure. To further investigate the molecular mechanism of the cigarette smoke-induced CXCL-8 production by human bronchial epithelial cells different inhibitors were used. It was concluded that purinergic P2X7 receptors and reactive oxygen species were involved. Interestingly, the inflammasome activator monosodium urate crystals (MSU) induced also the release of CXCL-8 and IL-1beta as well as IL-6, and the caspase-1 inhibitor, irreversible interleukin-1beta-converting enzyme (ICE) inhibitor Z-Val-Ala-Asp-dichlorobenzoate (Z-VADDCB), suppressed the cigarette smoke induced release of CXCL-8. In addition, cigarette smoke, CpGODN, LPS and MSU all increased the expression of caspase-1 and IL-1beta. In conclusion, our results demonstrate that cigarette smoke releases CXCL-8 from HBE-14o cells via TLR 4 and TLR9 and inflammasome activation.