Molecular medicine reports

hCLOCK induction by hypoxia promotes inflammatory responses by activating the NF‑κB pathway.

PMID 28098888


The expression and secretion of infla-mmation‑associated cytokines are induced by hypoxia. Circadian locomotor output cycles protein kaput (CLOCK) has previously been shown to activate the nuclear factor‑κB (NF‑κB) pathway, which is a key transcription factor during hypoxia. The present study evaluated the role of the NF‑κB pathway in the CLOCK‑induced inflammatory response. Under hypoxic conditions, the expression levels of NF‑κB and proinflammatory cytokines, including interleukin (IL)‑1, IL‑1β, IL‑6, intercellular adhesion molecule 1, cyclooxygenase 2 and tumor necrosis factor alpha, were significantly increased compared with under control conditions. Conversely, human umbilical vein endothelial cells (HUVECs) that were transfected with small hairpin RNA against human CLOCK exhibited reversed effects. Furthermore, inhibition of NF‑κB with pyrrolidine dithiocarbamate (PDTC) reduced the expression of proinflammatory cytokines in HUVECs treated under hypoxic conditions. In addition, the CLOCK‑induced inflammatory response was abolished with PDTC treatment. These findings suggest that the mechanism by which CLOCK induces inflammation mainly involves activation of the NF‑κB signaling pathway.