The carcinogenicity of nickel compounds has been well documented both in vitro and in vivo; however, the molecular mechanisms by which nickel compounds cause cancers are far from understood. Because suppression of apoptosis is thought to contribute to carcinogenesis, we investigated the mechanisms implicated in nickel-induced anti-apoptotic effect in human bronchial epithelial (Beas-2B) cells. We found that exposure of Beas-2B cells to nickel compounds resulted in increased cyclooxygenase-2 (COX-2) expression and that small interfering RNA (siCOX-2) knockdown of COX-2 expression resulted in increased cell sensitivity to nickel-triggered cell apoptosis, demonstrating that COX-2 induction has an anti-apoptotic effect on Beas-2B cells. Overexpression of IKKbeta-KM, a kinase inactive mutant of IKKbeta, blocked NF-kappaB activation and COX-2 induction by nickel compounds, indicating that activated NF-kappaB may be a mediator for COX-2 induction. To further explore the contribution of the NF-kappaB pathway in COX-2 induction and in protection from nickel exposure, mouse embryonic fibroblasts deficient in IKKbeta, IKKalpha, p65, and p50 were analyzed. Loss of IKKbeta impaired COX-2 induction by nickel exposure, whereas knockout of IKKalpha had a marginal effect. Moreover, the NF-kappaB p65, and not the p50 subunit, was critical for nickel-induced COX-2 expression. In addition, a deficiency of IKKbeta or p65 rendered cells more sensitive to nickel-induced apoptosis as compared with those in wild type cells. Finally, it was shown that reactive oxygen species H(2)O(2) were involved in both NF-kappaB activation and COX-2 expression. Collectively, our results demonstrate that COX-2 induction by nickel compounds occurs via an IKKbeta/p65 NF-kappaB-dependent but IKKalpha- and p50-independent pathway and plays a crucial role in antagonizing nickel-induced cell apoptosis in Beas-2B cells.