KLF12 inhibits lipopolysaccharide-induced inflammatory responses, oxidative stress, pyroptosis, and endoplasmic reticulum stress in human airway epithelial cells through inhibition of the NF-κB pathway.

Asthma is a common and frequent chronic disease in pediatrics with obvious pathological features, particularly inflammation, oxidative stress, pyroptosis, and endoplasmic reticulum (ER) stress. Some Krüppel-like factors (KLFs), such as KLF2, KLF4, KLF5, and KLF10, have been reported to be associated with several respiratory diseases, including asthma. However, the role of KLF12 in asthma pathogenesis is unknown. Based on the GEO analysis, KLF12 mRNA expression was reduced in asthma patients. We further assessed the role of KLF12 in protecting airway epithelial cells (BEAS-2B cells) against stimuli using an in vitro model of asthma. The results showed that lipopolysaccharide (LPS) stimulation caused a decrease in KLF12 expression. LPS-induced increase in the mRNA levels of inflammatory cytokines TNF-α, IL-6, and IL-8 were attenuated by KLF12 overexpression. LPS induced the production ROS and MDA and reduced the activities of enzymatic antioxidants SOD, CAT, and GSH-Px, which were prevented by KLF12 overexpression. KLF12 overexpression also blocked LPS-induced pyroptosis, as shown by decreased levels of IL-1β, IL-18, and LDH, as well as downregulated expression levels of pyroptosis-related proteins including NLRP3, ASC, cleaved caspase-1, and GSDMD-N. LPS-induced expression levels of ER stress markers GRP78, CHOP, p-eIF2α, and ATF-4 were inhibited by KLF12 overexpression. In addition, the protective effects of KLF12 on LPS-stimulated cells were enhanced by PDTC, an inhibitor of NF-κB. KLF12 knockdown showed an opposite effect to KLF12 overexpression. These results indicated that KLF12 suppressed LPS-induced inflammatory response, oxidative stress, pyroptosis, and ER stress, which were mediated by the inactivation of the NF-κB pathway.