NOD-like receptor family, pyrin domain-containing 3 (NLRP3) is one of the key components of the inflammasome. NLRP3 also participates in the regulation of fibrosis independent of the inflammasome. In this study, we analyzed the mechanism of upregulation of NLRP3 expression in A549 cells co-cultured with THP-1 macrophages under hypoxia. Upregulation of NLRP3 was suppressed after treatment with inhibitors of TGF-β receptor or p38, but not with inhibitors of the IL-1 receptor and SMAD3. The analysis of downstream molecules of TGF-β signaling in A549 cells co-cultured with THP-1 macrophages under hypoxia showed that TGFBR1 was upregulated and SMAD7 was downregulated. Taken together, these results suggest that the upregulation of NLRP3 in A549 cells is associated with deregulated TGF-β signaling and that the interaction between NLRP3 and TGF-β signaling plays a fundamental role in fibrogenesis.