The newly emerging coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China, but has rapidly spread all over the world. Some COVID-19 patients encounter a severe symptom of acute respiratory distress syndrome (ARDS) with high mortality. This high severity is dependent on a cytokine storm, most likely induced by the interleukin-6 (IL-6) amplifier, which is hyper-activation machinery that regulates the nuclear factor kappa B (NF-κB) pathway and stimulated by the simultaneous activation of IL-6-signal transducer and activator of transcription 3 (STAT3) and NF-κB signaling in non-immune cells including alveolar epithelial cells and endothelial cells. We hypothesize that IL-6-STAT3 signaling is a promising therapeutic target for the cytokine storm in COVID-19, because IL-6 is a major STAT3 stimulator, particularly during inflammation. We herein review the pathogenic mechanism and potential therapeutic targets of ARDS in COVID-19 patients.

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The Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway is an important signaling pathway of interferons and cytokines. We examined the activation of STAT proteins induced by interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), or erythropoietin (EPO) using the human leukemia cell line, UT-7, which requires these cytokines for growth. IL-3, GM-CSF, and EPO induced DNA-binding activity to the oligonucleotides corresponding to the sis-inducible elements (SIE) of c-fos, in addition to the ␤-casein promoter (␤-CAP), SIE-and ␤-CAP-binding proteins were identical to Stat1␣ and Stat3 complex and to Stat5 protein, respectively. This indicates that IL-3, GM-CSF, and EPO commonly activated Stat1␣, Stat3, and Stat5 proteins in UT-7. However, EPO hardly activated Stat1␣ and Stat3 in UT-7/GM, which is a subline of UT-7 that grows slightly in response to EPO. Transfection studies revealed that UT-7/GM cells constitutively expressing Stat1␣, but not Stat3, can grow as well in response to EPO as GM-CSF, suggesting that Stat1␣ is involved in the EPO-induced proliferation of UT-7. Thus, although Stat1␣, Stat3, and Stat5 proteins are activated by GM-CSF, IL-3, and EPO, our data suggest that each STAT protein has a distinctive role in the actions of cytokines.

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