Hypoxia/Reoxygenation Differentially Modulates NF-κB Activation and iNOS Expression in Astrocytes and Microglia

Hypoxia/ischemic brain injury accompanies an inflammatory response involving an activation of glial cells. This study, using an in vitro model, investigated the signaling mechanisms mediating hypoxic responses of the two glial cell types (astrocytes and microglia) in relation to the expression of inducible nitric oxide synthase (iNOS). In cultures of rat brain microglia and astrocytes, hypoxia (8 h) followed by reoxygenation (24 h) (H/O) had little (microglia) or no (astrocytes) effect on the expression of iNOS. However, H/O elicited opposite effects on lipopolysaccharide (LPS) induction of iNOS in the two cell types: it potentiated LPS induction of iNOS in microglia but inhibited this response in astrocytes. Similar differential effects of hypoxia were observed on the production of tumor necrosis factor-α (TNFα). In contrast, there was an upregulation of hemoxygenase- 1 (HO-1), a counter-regulatory pathway, with astrocytes showing a bigger induction than microglia. While hypoxic activation of mitogen-activated protein kinases (MAPKs) was similar in the two glial types, the activation pattern of NFκB was clearly different: hypoxia stimulated the activation of NFκB pathway and NFκB-dependent transcription in microglia but not in astrocytes. Lastly, the two cell types displayed differential vulnerabilities to hypoxia-induced cell death, the astrocytes being relatively more resistant than microglia.