1498-P: Intermittent Hypoxia Increased the Expression ofIL-1ß, IL-6, and IL-8 in Human Monocytes through the Downregulation of MicroRNA-146a

Sleep apnea syndrome (SAS) is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]) and is a risk factor for systemic inflammation. Serum inflammation markers such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, IL-10, and C-X-C motif chemokine ligand 10 (CXCL10) in SAS patients have been reported to be elevated. However, the details of why IH leads to induce the elevations remain unclear. We investigated inflammation-related transcripts in human monocytes (HL-60 and THP-1 cells) exposed to IH by real-time RT-PCR and found that IL-1 β, IL-6, and IL-8 mRNAs were significantly increased. ELISA confirmed that IL-1β, IL-6, and IL-8 in the HL-60 and THP-1 culture media were significantly increased by IH (P=0.011 and 0.0339 in IL-1β, P=0.0419 and 0.369 in IL-6, P<0.0001 and <0.0001 in IL-8, respectively). We next investigated promoter activities of the genes and revealed that they were not increased by IH. On the other hand, target mRNA search of microRNA (miR)s revealed that the mRNAs have a potential target sequence for miR-146a. The miR-146a level of IH-treated cells was significantly decreased than that of normoxia-treated cells. Thus, we introduced miR-146a mimic and non-specific control RNA (miR-146a mimic NC) into HL-60 and THP-1 cells and measured the mRNA and protein levels of IL-1β, IL-6, and IL-8. The IH-induced expression of IL-1β, IL-6, and IL-8 was abolished by introduction of miR-146a mimic but not by miR-146a mimic NC. Our results demonstrate that IH stress up-regulates the levels of IL-1β, IL-6, and IL-8 in human monocytes to accelerate systemic inflammation including diabetes through the miR-146a mediated mechanism, resulting in onset or aggravation of systemic inflammation.