The protozoan parasite Giardia duodenalis inhabits the upper small intestine of mammals, including humans, and causes a disease known as giardiasis, which can lead to diarrhea, abdominal cramps, and bloating. G. duodenalis was known as a causative factor of intestinal epithelial cell (IEC) apoptosis. Cyclooxygenase-2 (COX-2) has been identified as an influencing factor of pathogen infection by participating in immune response, while its role in host defense against Giardia infection is not clear. Here, we initially observed the involvement of COX-2 in the regulation of Giardia-induced IEC apoptosis. Inhibition of COX-2 activity could promote Giardia-induced reduction of IEC viability, increase of reactive oxygen species (ROS) production, and decrease of nitric oxide (NO) release, which would exacerbate IEC apoptosis. In addition, during Giardia-IEC interactions, COX-2 inhibition was able to accelerate caspase-3 activation and poly(ADP-ribose) polymerase (PARP) cleavage and inhibit the expressions of some anti-apoptotic proteins like cIAP-2 and survivin. In contrast, COX-2 overexpression could reduce Giardia-induced IEC apoptosis. We further investigated the regulatory mechanisms affecting COX-2 expression in terms of anti-apoptosis. The results showed that p38/ERK/AKT/NF-κB signaling could regulate COX-2-mediated ROS/NO production and anti-IEC apoptosis during Giardia infection. We also found that COX-2-mediated anti-IEC apoptosis induced by Giardia was related to Toll-like receptor 4 (TLR4)-dependent activation of p38-NF-κB signaling. Collectively, this study identified COX-2 as a promoter for apoptotic resistance during Giardia-IEC interactions and determined the potential regulators, furthering our knowledge of anti-Giardia host defense mechanisms.

Liu Lin

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