Activation of the JAK-STAT pathway by reactive oxygen species

TLDR

Reactive oxygen species contribute to the pathogenesis of diseases such as ARDS, Parkinson’s, pulmonary fibrosis, and Alzheimer’s, and can induce immediate‑early genes like c‑fos and c‑myc in mammalian cells. In fibroblasts and A‑431 cells, H₂O₂ rapidly activates STAT1/3 via JAK2/TYK2 within 5 min, an effect blocked by antioxidants, not requiring new protein synthesis, and ROS also mediates PDGF‑induced STAT activation.

Abstract

Reactive oxygen species (ROS) play an important role in the pathogenesis of many human diseases, including the acute respiratory distress syndrome, Parkinson’s disease, pulmonary fibrosis, and Alzheimer’s disease. In mammalian cells, several genes known to be induced during the immediate early response to growth factors, including the protooncogenes c- fos and c- myc, have also been shown to be induced by ROS. We show that members of the STAT family of transcription factors, including STAT1 and STAT3, are activated in fibroblasts and A-431 carcinoma cells in response to H 2 O 2 . This activation occurs within 5 min, can be inhibited by antioxidants, and does not require protein synthesis. STAT activation in these cell lines is oxidant specific and does not occur in response to superoxide- or nitric oxide-generating stimuli. Buthionine sulfoximine, which depletes intracellular glutathione, also activates the STAT pathway. Moreover, H 2 O 2 stimulates the activity of the known STAT kinases JAK2 and TYK2. Activation of STATs by platelet-derived growth factor (PDGF) is significantly inhibited by N-acetyl-l-cysteine and diphenylene iodonium, indicating that ROS production contributes to STAT activation in response to PDGF. These findings indicate that the JAK-STAT pathway responds to intracellular ROS and that PDGF uses ROS as a second messenger to regulate STAT activation.