LPS Induces Hypoxia-Inducible Factor 1 Activation in Macrophage-Differentiated Cells in a Reactive Oxygen Species–Dependent Manner

Abstract

A prominent feature of various inflamed and diseased tissue is the presence of low oxygen tension (hypoxia). Effector cells of the innate immune system must maintain their viability and physiologic functions in a hypoxic microenvironment. Monocytes circulating in the bloodstream differentiate into macrophages. During this process, cells acquire the ability to exert effects at hypoxic sites of inflammation. The transcription factor hypoxia-inducible factor 1 (HIF-1) mediates adaptive responses to reduced oxygen availability. In this study, we demonstrated that lipopolysaccharide (LPS) induces HIF-1 activation by enhancing both HIF-1alpha protein expression through a translation-dependent pathway and HIF-1alpha transcriptional activity in THP-1 human myeloid cells that have undergone macrophage differentiation but not in undifferentiated monocytic THP-1 cells. LPS-induced HIF-1 activation was blocked by treatment with antioxidant (N-acetylcysteine or thioredoxin-1), NADPH oxidase inhibitor (diphenyleneiodonium), indicating that reactive oxygen species generated in response to LPS are essential in this process. LPS-mediated activation of HIF-1 was independent of NF-kappaB activity. LPS-induced ROS generation and HIF-1 activation required the expression of Toll-like receptor 4 or myeloid differentiation factor (MyD) 88, thus providing a molecular basis for the selective activation of HIF-1 in differentiated THP-1 cells.

Macrophage Oxygen Sensing Modulates Antigen Presentation and Phagocytic Functions Involving IFN-γ Production through the HIF-1α Transcription Factor

“…Hypoxia-stimulated macrophages could mimic M1 classically activated macrophages in a similar manner as LPS-activated macrophages. In fact, the classical activation triggers proinflammatory cytokine secretion, which match our data on the increment of the proinflammatory cytokines IFN-␥ and IL-12, together with the increase of IL-6, reactive oxygen species and NO synthesis previously described (53,59,62,63). Therefore, hypoxia could be acting as a priming step preparing the macrophage for an active response.…”

“…Therefore, hypoxia could be acting as a priming step preparing the macrophage for an active response. In addition to hypoxia, LPS or other inflammatory signals may act either synergistic or antagonistically inducing further activation or inhibition of the macrophage (18,62,64), in particular, in the development of LPS-induced sepsis (53), atheroma plaque formation or tissue remodeling. Further studies on these responses are needed to understand the cross-talk between the different pathways involved in macrophage modulation.…”

Macrophage Glucose-6-Phosphate Dehydrogenase Stimulates Proinflammatory Responses with Oxidative Stress

“…Although we observed that inhibition of NF-B greatly suppressed G6PD-induced proinflammatory responses, we could not exclude the possibility that other transcription factors also contribute to G6PD-induced proinflammatory responses in macrophages. For instance, several transcription factors, such as Sp1, AP-1, p53, and HIF-1, have been reported to be redox-responsive transcription factors that appear to be differentially activated by oxidative stresses to exert proinflammatory responses (52,53).…”

Hypoxia-inducible factors: key regulators of myeloid cells during inflammation

“…The proinflammatory cytokines TNF-α and IL-1β promote HIF-1α accumulation in an NF-κB-dependent manner (33)(34)(35). Bacterial products, such as LPS, can also stabilize HIF-1α under normoxia through multiple pathways, such as NF-κB (36,37), ROS (38), PHDs (39), and MAPKs (40). On the other hand, hypoxic responses can also be HIF independent.…”