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NF‑Κb Regulates HSF1 and C‑Jun Activation in Heat Stress‑Induced Intestinal Epithelial Cell Apoptosis

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NF‑Κb Regulates HSF1 and C‑Jun Activation in Heat Stress‑Induced Intestinal Epithelial Cell Apoptosis 3388 MOLECULAR MEDICINE REPORTS 17: 3388-3396, 2018 NF‑κB regulates HSF1 and c‑Jun activation in heat stress‑induced intestinal epithelial cell apoptosis JUN LI1,2*, YANAN LIU3*, PENGKAI DUAN4*, RONGGUO YU2, ZHENGTAO GU5, LI LI5, ZHIFENG LIU4 and LEI SU1,4 1Graduate School, Southern Medical University, Guangzhou, Guangdong 510515; 2Department of Critical Care Medicine, Fujian Provincial Hospital, Fuzhou, Fujian 350000; 3Department of Intensive Care Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515; 4Department of Intensive Care Unit, Key Laboratory of Tropical Zone Trauma Care and Tissue Repair of PLA, General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010; 5Department of Intensive Care Unit, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510630, P.R. China Received July 18, 2016; Accepted July 13, 2017 DOI: 10.3892/mmr.2017.8199 Abstract. Heat stress may induce intestinal epithelial cell apop- Introduction tosis; however, the molecular mechanisms have not yet been identified. The present study used IEC‑6 rat small intestinal Intestinal epithelial cells are crucial components of the intes- epithelial cells to investigate heat stress-induced production tinal mucosal barrier, and damage to these cells increases of reactive oxygen species (ROS), which may be involved in the permeability of this barrier, which may lead to increased nuclear factor (NF)-κB activation during heat stress. IEC‑6 translocation of gut-derived bacterial endotoxins (1). Previous cells were transfected with NF-κB p65‑specific small inter- studies on the effects of heat stress on these cells have reported fering RNA (siRNA), and observed a significant increase a significant level of apoptosis in the rat small intestine (2,3). in cell apoptosis and caspase-3 cleavage; however, in cells Indeed, apoptosis in the small intestine was demonstrated to transfected with adenovirus that constitutively overexpressed serve a major role in the pathogenesis of heat stroke (2,3). p65, the opposite results were obtained. Furthermore, p65 Heat stress may induce the production of reactive oxygen knockdown increased the heat stress-induced expression and species (ROS), which may lead to cellular dysfunction and activity of heat shock transcription factor 1 (HSF1); conversely, cell death (3-5). Nuclear factor (NF)‑κB was previously p65 overexpression slightly decreased HSF1 activity. The reported to be induced by a multitude of stimuli, such as levels of heat stress-induced c-Jun phosphorylation were cytokines, oxidative stress or thermal stress (6). A previous also examined: Knockdown of p65 resulted in a reduction of study demonstrated that NF-κB is activated in response to c-Jun phosphorylation, whereas p65 overexpression resulted heat stress in HeLa human cervical cancer cells (6). Many in increased phosphorylation. Furthermore, siRNA‑mediated inducers of NF-κB expression may be inhibited by anti- knockdown of HSF1 in IEC‑6 cells significantly increased oxidants, which suggested that ROS may modulate the signal heat stress‑induced apoptosis. Cells pretreated with c‑Jun transduction pathway leading to NF-κB activation (7,8). peptide, an inhibitor of c‑Jun activation, exhibited a significant However, the role of ROS heat stress-induced NF-κB acti- reduction in apoptosis. These findings indicated that heat vation in IEC-6 rat small intestinal epithelial cells remains stress stimulation in IEC-6 cells induced the pro-apoptotic unclear. Cultured IEC‑6 cells are similar to the mature intes- role of NF-κB by regulating HSF1 and c‑Jun activation. tinal epithelium (3), and were used as a model to investigate the mechanisms of intestinal epithelial cell survival and apoptosis. The heterodimeric NF-κB complex comprises two DNA binding subunits, p50 and p65, which may form either homo- Correspondence to: Professor Lei Su, Department of Intensive or heterodimers (9). NF‑κB signaling is a transcriptional Care Unit, Key Laboratory of Tropical Zone Trauma Care and Tissue regulator of several genes that are involved the inflammatory Repair of PLA, General Hospital of Guangzhou Military Command, 111 Liu Hua Road, Guangzhou, Guangdong 510010, P.R. China response, cell growth, cell survival and apoptosis (9,10). A E‑mail: [email protected] number of studies have reported that NF-κB activation may downregulate proapoptotic signaling and thus prevent apop- *Contributed equally tosis in many cells types (10,11). By contrast, other studies have demonstrated that NF-κB activation may by an inducer of Key words: heat stress, apoptosis, reactive oxygen species, nuclear apoptosis (12,13). However, the mechanisms underlying heat factor κB, heat shock transcription factor 1, c-Jun stress-induced apoptosis in IEC-6 cells and the involvement of NF-κB activation are still unknown. LI et al: HEAT STROKE AND CELL APOPTOSIS 3389 Heat shock transcription factor 1 (HSF1) is a master 10 µM DCFH‑DA for 30 min at 37˚C in the dark. Following regulator of the genes that encode molecular chaperones and this, the cells were harvested by trypsin, the supernatants was serves a role in the attenuation of apoptosis induced by multiple removed by centrifugation (1,000 x g for 3 min at room temper- factors (14,15). Upon heat shock, HSF1 rapidly translocates ature) and resuspended in serum-free DMEM culture medium into the nucleus and exhibits the properties of a stable trimer three times. The fluorescence intensity was determined using which correlates with the acquisition of DNA binding activity; a flow cytometer (FACSCanto™ II; BD Biosciences, San Jose, furthermore, the transcriptionally active form of HSF1 CA, USA) and analyzed using FlowJo software version 9.0 becomes inducibly phosphorylated (16). Previous studies have (FlowJo LLC, Ashland, OR, USA). reported interactions between HSF1 and NF-κB, which serve opposite roles in cytoprotection and cell injury (17). Flow cytometric analysis of cell apoptosis. Cell apoptosis The signal-transducing transcription factor c-Jun, also was analyzed by flow cytometry with annexin V‑fluorescein known as activating protein 1 (AP1), has previously been isothiocyanate (FITC) Apoptosis Detection kit (Invitrogen; reported to serve a role in cell cycle progression, differentiation Thermo Fisher Scientific, Inc.), according to the manufacturer's and transformation, as well as apoptosis (18,19). c‑Jun protein protocol. Briefly, cells were either kept untreated or incubated activity is regulated by phosphorylation at specific sites; for at 43˚C for 20, 40, 60, 80 min, followed by an additional incu- example, Ser63 phosphorylation in the transactivation domain bation at 37˚C for 6 h. Control cells were always incubated leads to an increased ability of c-Jun to activate the transcrip- at 37˚C. IEC‑6 cells (1x106) were collected, washed in ice tion of target genes (20). Previous studies have demonstrated cold PBS and resuspended in the binding buffer containing that c-Jun is able to physically interact with NF-κB p65 through 5 µl annexin V-FITC (5 µg/ml). Following incubation at room the Rel homology domain (21). Nevertheless, whether NF‑κB temperature for 10 min, the buffer was removed by centrifu- can interact with HSF1 and c‑Jun, and thereby influence IEC‑6 gation (1,000 x g, 3 min, room temperature) and cells were cell apoptosis, still remains unknown. resuspended in reaction buffer containing 10 µl propidium Results from the present study demonstrated that heat iodide (PI; 5 µg/ml) for 10 min at room temperature. Flow stress-induced increases of ROS levels may lead to NF-κB cytometric analysis was immediately performed to detect activation, which in turn may activate caspase-3 and, thus, apoptosis (FACSCanto™ II; BD Biosciences), The combina- apoptosis in IEC‑6 cells. In addition, a putative role for NF‑κB tion of Annexin V-FITC and propidium iodide allows for the in the regulation of HSF1 and c-Jun activation induced by distinction between early apoptotic cells (Annexin V-FITC heat stress treatment was investigated. This study also aimed positive), late apoptotic and/or necrotic cells (Annexin V-FITC to examine whether HSF1 might prevent apoptosis and c-Jun and propidium iodide positive), and viable cells (unstained). activation‑induced apoptosis in the same experimental settings. The fluorescence intensity was analyzed using FlowJo soft- ware version 9.0 (FlowJo LLC, Ashland, OR, USA). Materials and methods Small interfering (si)RNA transfection. siRNAs for NF-κB Cell culture and treatments. Approximately 2x106 IEC-6 p65 and HSF1 were designed and synthesized by Shanghai cells (ATCC, Manassas, VA, USA) were grown as a mono- GenePharma Co. Ltd. (Shanghai, China). The sequence of layer in Dulbecco's Modified Eagle's Medium (DMEM) each siRNA and the negative control (non-targeting siRNA) supplemented with 10% heat inactivated fetal bovine serum are shown in Table I. Prior to transfection, 1x105 IEC-6 cells (FBS) (Invitrogen; Thermo Fisher Scientific, Inc., Waltham, were plated onto a 6‑well plate (Nest Biotechnology Co., Ltd., MA, USA), 100 U/ml of penicillin, and 100 µg/ml of strepto- Wuxi, China) and incubated for 24 h to 30‑50% confluence mycin (Invitrogen; Thermo Fisher Scientific, Inc.) at 37˚C in at 37˚C. Cells were transfected with 1 µM siRNA (all a humidified atmosphere of 5% CO2 and 95% air. To induce siRNAs were used at this concentration) using siRNAMate heat stress, culture dishes were placed into a circulating water Transfection Reagent (Shanghai GenePharma Co. Ltd.) and bath at 43±0.5˚C for indicated times; control cells were held incubated for 12 h at 37˚C, according to the manufacturer's at 37±0.5˚C. Following heat‑stress culture, the media was protocol. Cells were incubated following 48‑72 h at 37˚C for replaced and cells were further incubated at 37˚C for 0, 2, 6 further experiments. and 12 h. Adenoviral infection. Adenoviruses (Ad) that constitutively Measurement of ROS levels. Levels of intracellular ROS overexpressed p65 (Ad-p65) or empty construct (Ad-empty) were assessed using a ROS assay kit (Beyotime Institute of were constructed by Vigene Biosciences (Jinan, China).
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