FIG. 1.

IL‐6 signaling (classical vs. trans‐signaling) in COVID‐19. Excessive inflammatory cytokine signaling, particularly through IL‐6, is thought to be an important factor in the pathogenesis of COVID‐19. IL‐6 induces downstream signaling through JAK/STAT activation through two pathways. One is classical IL‐6 signaling through IL‐6 binding to the ligand‐binding alpha subunit of its receptor (gp80/IL‐6Rα) and subsequently recruiting the signaling beta subunit (gp130) to produce downstream signaling. This pathway is thought to be anti‐inflammatory and to promote liver regeneration. The other is trans‐signaling that occurs with IL‐6 binding to a soluble form of the receptor alpha subunit. ADAM17, which is typically increased in inflammatory conditions, cleaves the membrane‐bound IL‐6Rα, increasing sIL‐6R and creating opportunity for formation of the IL‐6/sIL‐6R complex, which then interacts with gp130 on target cells that may not express membrane‐bound IL‐6Ra. IL‐6 trans‐signaling is thought to be the major route of IL‐6 signaling to LSECs and has been implicated in endotheliopathy (proinflammatory and procoagulant state) in COVID‐19. The sIL‐6R levels are increased in COVID‐19, ¹⁴³ with a likely result of increased trans‐signaling. Abbreviation: gp80, interleukin‐6 receptor ligand‐binding domain.