Lung cancer (LC) is the most common and lethal form of cancer worldwide and in Australia alone accounts for approximately 7,500 deaths annually. A causal correlation between lung cancer and cigarette smoking has been well established, however only 10-15% of smokers develop LC, suggesting the presence of other ill-defined genetic, epigenetic and/or environmental factors which predispose certain individuals to LC. Lung inflammation is the hallmark of all LC patients either from smoking and/or from genetic abnormalities; however the inflammatory signalling mechanisms associated with the molecular pathogenesis of lung carcinogenesis are poorly understood. In this regard, the interleukin (IL)-6 cytokine family, which signals through the shared gp130 signal-transducing receptor subunit, has been implicated in promoting a host of pathological responses including inflammation and LC. The engagement of gp130 triggers the activation of several downstream signalling pathways, in particular the latent transcription factor signal transducer and activator of transcription (Stat)-3 which plays a vital role in regulating pro-inflammatory and oncogenic cellular processes. Notably, an increased activation of Stat3 is linked with LC. However, the mechanisms leading to, and the downstream consequences of, increased Stat3 activity in human lung diseases are ill defined. Therefore, we utilized several human cancer cell lines to investigate the molecular consequences of cooperation between gp130 signalling and LC risk factors in in vitro. Our data showed, for the first time, that IL-6 and potent cigarette smoke carcinogen, NNK, can modulate endogenous gp130/Stat3 signalling in human LC cell lines at both the mRNA and protein level within an acute period, regardless of their constitutively active Stat3 level. These results will therefore provide a significant and original contribution to our fundamental understanding of the mechanisms involved in LC that will potentially strengthen the translational impact of early detection and treatment of the disease in the clinic.