PMID- 36223757 OWN - NLM STAT- MEDLINE DCOM- 20221205 LR - 20230213 IS - 1423-0097 (Electronic) IS - 1018-2438 (Linking) VI - 183 IP - 12 DP - 2022 TI - IL-12 Contributes to the Development of Asthma by Targeting HIF-1alpha/NLRP3 Pathway through Runx3. PG - 1231-1240 LID - 10.1159/000526803 [doi] AB - INTRODUCTION: The aim of the study was to determine the role and mechanism of runt-related transcription factor 3 (Runx3) in the development of asthma. METHODS: An asthma mouse model was constructed and validated by hematoxylin-eosin analysis of lung tissue and noninvasive enhanced pause (Penh) evaluation of airway hyperresponsiveness. Then, the levels of Runx3 and interleukin (IL)-12 in peripheral blood and lung tissue were detected by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. By use Runx3+/- mice, the effect of Runx3 downregulation on ovalbumin (OVA)-induced asthma was investigated. After stimulated by different doses of IL-12, the expressions of Runx3, hypoxia inducible factor-1alpha (HIF-1alpha), and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) in BEAS-2B cells were tested through Western blot and immunofluorescence. Subsequently, BEAS-2B cells treated with 20 ng/mL IL-12 were divided into control, Runx3 overexpression negative control, Runx3 overexpression, HIF-1alpha inhibitor, and Runx3 overexpression + HIF-1alpha agonist groups. The Western blot, immunofluorescence, and ELISA indicators were tested repeatedly. RESULTS: The increased number of inflammatory cells and Penh value confirmed the success of the asthma mouse model. IL-12 expression was significantly increased, and Runx3 was reduced in asthma mice compared with wild-type mice. Meanwhile, the level of immunoglobulin E (IgE) in serum, cytokines in bronchoalveolar lavage fluid, and IL-12, HIF-1alpha, NLRP3 in the lung were significantly elevated in Runx3+/- mice. With the increase of IL-12 concentration, Runx3 protein expression decreased, while HIF-1alpha and NLRP3 expression increased. Further mechanistic studies suggest that Runx3 ameliorates IL-12-induced BEAS-2B injury by inhibiting HIF-1alpha/NLRP3 pathway. CONCLUSION: These results suggested that IL-12 contributes to the development of asthma by targeting HIF-1alpha/NLRP3 pathway through Runx3, thus providing a novel strategy for asthma therapy. CI - (c) 2022 S. Karger AG, Basel. FAU - Sun, Yinghong AU - Sun Y AD - Department of Pediatrics, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China. FAU - Xia, Tian AU - Xia T AD - Department of Pediatrics, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China. FAU - Ma, Jingfang AU - Ma J AD - Department of Child Healthcare, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China. FAU - Sun, Yunxiao AU - Sun Y AD - Department of Pediatrics, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China. LA - eng PT - Journal Article DEP - 20221012 PL - Switzerland TA - Int Arch Allergy Immunol JT - International archives of allergy and immunology JID - 9211652 RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 187348-17-0 (Interleukin-12) RN - 9006-59-1 (Ovalbumin) RN - 0 (Nlrp3 protein, mouse) SB - IM MH - Mice MH - Animals MH - *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/analysis MH - Interleukin-12/adverse effects/analysis MH - Signal Transduction MH - *Asthma/metabolism MH - Lung/metabolism MH - Bronchoalveolar Lavage Fluid/chemistry MH - Ovalbumin/adverse effects MH - Disease Models, Animal OTO - NOTNLM OT - Asthma OT - HIF-1alpha/NLRP3 OT - Inflammation OT - Interleukin-12 OT - Runx3 EDAT- 2022/10/13 06:00 MHDA- 2022/12/06 06:00 CRDT- 2022/10/12 18:23 PHST- 2022/07/04 00:00 [received] PHST- 2022/08/25 00:00 [accepted] PHST- 2022/10/13 06:00 [pubmed] PHST- 2022/12/06 06:00 [medline] PHST- 2022/10/12 18:23 [entrez] AID - 000526803 [pii] AID - 10.1159/000526803 [doi] PST - ppublish SO - Int Arch Allergy Immunol. 2022;183(12):1231-1240. doi: 10.1159/000526803. Epub 2022 Oct 12.