Toll-like receptors (TLRs) play a crucial role in the immune and inflammatory responses induced by identifying invasion of pathogenic microorganisms and endogenous danger signals. Increase the expression of TLR4 in ischemic tissue injury and participate in chronic disease, severe symptoms of inflammation. Our previous study results show that stress, which is hypoxic hypoxia-inducible factor 1 (HIF-1) an average increase of the level of transcription of the macrophage expression of TLR4. In this study, we analyzed the upstream signal path of TLR4 expression has contributed to hypoxic stress increase. Whether the expression of PI3K and Akt inhibitor treatment or siRNA of Akt protein removal, and increased exposure to hypoxia and cobalt chloride to block the macrophages of TLR4 mRNA and protein. Stress nuclear accumulation of HIF-1α in hypoxia prior to the phosphorylation of Akt. Of PI3K inhibitor (LY294002) attenuated by cobalt chloride-induced nuclear accumulation and transcriptional activation of HIF-1α. In addition, HIF-1α-mediated increase of TLR4 expression LY294002. In addition, sulforaphane, activation and subsequent PI3K/AKT inhibition of nuclear accumulation of HIF-1α transcriptional activity inhibition of hypoxia and CoCl2-induced TLR4 mRNA and protein expression. However, P38 of HIF-1α activation and expression of TLR4 was involved in the macrophage hypoxia-inducible stress. Taken together, our results show that, of PI3K/AKT hypoxic stress-induced expression of TLR4, at least part of the regulation of HIF-1 activation. These show a new mechanism that regulates the expression of TLR4 hypoxic stress, and provides a therapeutic target in stress-related diseases and chronic hypoxia.