Abstract
The molecular mechanisms by which hypoxia contributes to prostatic chronic inflammation (PCI) remain largely unknown. Because hypoxia stimulates the transcriptional activity of NF-κB, which “primes” cells for inflammasome activation by inducing the expression of NLRP3 or AIM2 receptor and pro-IL-1β, we investigated whether hypoxia could activate the NLRP3 and AIM2 inflammasome in human normal prostate epithelial cells (PrECs) and cancer cell lines. Here we report that hypoxia (1% O2) treatment of PrECs, prostate cell lines, and a macrophage cell line (THP-1) increased the levels of NLRP3, AIM2, and pro-IL-1β. Further, hypoxia in cells potentiated activation of the NLRP3 and AIM2 inflammasome activity. Notably, hypoxia “primed” cells for NLRP3 and AIM2 inflammasome activation through stimulation of the NF-κB activity. Our observations support the idea that hypoxia in human prostatic tumors contributes to PCI, in part, by priming cells for the activation of NLRP3 and AIM2 inflammasome.
Highlights
The availability of optimum levels of oxygen to cells and tissues in vivo is critical for normal cellular homeostasis [1, 2]
Because hypoxia in prostatic tumors is associated with chronic inflammation and a poor outcome for prostate cancer patients [19, 21, 32, 33], we investigated whether hypoxia in human prostate epithelial cells (PrECs), prostate cancer and myeloid cell lines promotes NLRP3 and AIM2 inflammasome activation
Because hypoxia-induced activation of NF-κB activity in cells results in transcriptional activation of genes that encode for the proinflammatory cytokines [14, 17, 22] and epithelial cells are exposed to chronic or cycling hypoxia in prostate tumors [19, 21], we investigated whether hypoxia could activate the NF-κB activity and “prime” PrECs for activation of the NLRP3 or AIM2 inflammasome activity
Summary
The availability of optimum levels of oxygen to cells and tissues in vivo is critical for normal cellular homeostasis [1, 2]. The availability of sub-optimal levels of oxygen (or lack of it) to cells due to an infectionassociated inflammation, injury, or noxious agents contributes to cell death and chronic inflammation in a variety of human diseases, including cancers [3,4,5,6,7,8]. The oxygen-responsive hypoxia-inducible factor (HIF), which consists of an unstable α subunit and a stable β subunit, plays an important role in adaptation to hypoxia through transcriptional regulation of a set of genes that encode for survival proteins [1, 2]. In the presence of oxygen, members of the conserved Egl-Nine (EGLN) gene family (such as EGLN1, EGLN2 and EGLN3) that encode for prolyl hydroxylases in most cell types hydroxylate the HIFα subunit [1, 2]. Under low-oxygen conditions (e.g, at 1% O2), HIF-1α is stabilized and it stimulates the transcription of a set of target genes [12, 13] and activates the transcriptional activity of NF-κB [14,15,16,17], a master regulator of genes that encode for proinflammatory cytokines such as IL-1β and IL-18 [14, 17]
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