IL-6 signaling in myeloma and CD38 regulation. The cytokine IL-6 binds the receptors IL-6 receptor alpha (IL-6RA) and GP130 to activate JAK1 and JAK2 kinases that phosphorylate STAT3 and to a lesser extent STAT1, resulting in their dimerization and nuclear translocation. Ogiya et al find that STAT3 inhibits CD38 expression, whereas STAT1 increases it, and STAT3 knockout results in an upregulation and activation of STAT1. Increased CD38 expression results in more ADCC. Lines with arrows or blocks do not necessarily represent direct interactions. NK, natural killer.