Intracellular IL-33 attenuates extracellular IL-33-induced cholangiocarcinoma cell proliferation and invasion via NF-κB and GSK-3β pathways

Abstract

Background/Aim: The functions of interleukin 33 (IL-33) in cholangiocarcinoma (CCA) are unclear. This study aimed to evaluate the roles of IL-33 in CCA progression. Materials and Methods: The effect of intracellular IL-33 using shIL-33 knocked down KKU-055 (IL-33KD-KKU-055) compared to parental (Pa) KKU-055 and extracellular IL-33 using recombinant human IL-33 (rhIL-33) treatment on the proliferation and invasion of CCA cells grown in 3D cultures was studied. Relevant markers were determined by western blot or ELISA. Results: IL-33KD-KKU-055 cells showed increased proliferation and invasion in 3D cultures compared to Pa-KKU- 055 cells, with NF-κB and IL-6 up-regulation. Treatment with 2 ng/ml rhIL-33 promoted Pa-KKU-055 cell proliferation by inducing NF-κB and IL-6 expressions. Upon GSK-3β inactivation and increased nuclear full-length IL-33 (flIL-33), 20 ng/ml rhIL-33 had no effect on proliferation. Both 2 and 20 ng/ml rhIL-33 induced proliferation and invasion of IL-33- negative KKU-213 cells in 3D cultures, as well as NF-κB and IL-6 up-regulation. Conclusion: Intracellular and extracellular IL-33 have distinct roles in the mechanisms of CCA progression.