Hypoxia and
inflammation often develop concurrently in numerous diseases, and the influence of
hypoxia on natural evolution of inflammatory responses is widely accepted.
Glucocorticoid-induced leucine zipper (GILZ) is thought to be an important mediator of anti-inflammatory and immune-suppressive actions of
glucocorticoid (GC). However, whether GILZ is involved in hypoxic response is still unclear. In this study, we investigated the effects of hypoxic exposure and/or the administration of
dexamethasone (Dex), a synthetic GC on GILZ expression both in vitro and in vivo, and further explored the relationship between GILZ and proinflammatory
cytokines IL-1β,
IL-6, and TNF-α under normoxic and hypoxic conditions. We found that
hypoxia not only remarkably upregulated the expression of GILZ, but also significantly enhanced Dex-induced expression of GILZ in macrophages and the spleen of rats. ERK activity is found involved in the upregulation of GILZ induced by
hypoxia. Inhibiting the expression of GILZ in RAW264.7 cells using specific GILZ
small interfering RNA led to a significant increase in
mRNA production and
protein secretion of IL-1β and
IL-6 in
hypoxia and abrogated the inhibitory effect of Dex on expression of IL-1β and
IL-6 in
hypoxia. We also found that adrenal
hormones played pivotal roles in upregulation of GILZ expression in vivo. Altogether, data presented in this study suggest that GILZ has an important role not only in adjusting adaptive responses to
hypoxia by negatively regulating the activation of macrophages and the expression of proinflammatory
cytokines, but also in mediating the anti-inflammatory action of GC under hypoxic conditions.