IL-6 inhibits TLR-signaling in CLL cells. (A) Simultaneous treatment of isolated CLL cells with IL-2 and TLR7 agonists (such as the imidazoquinoline resiquimod) increases the expression of costimulatory molecules (eg, CD83) and inflammatory cytokines (eg, TNF-α), and induces rapid CLL cells proliferation. (B) Contrarily, treatment of stromal-cocultured CLL cells with IL-2 and TLR7 agonists slows down cell proliferation and induces a “state of tolerance” to TLR7 stimuli. Briefly, stromal cells produce and release high levels of IL-6, which binds to IL-6 receptor (IL-6R) on CLL cells and stimulates phosphorylation and activation of signal transducer and activator of transcription 3 (STAT3). Phosphorylated STAT3 translocates to the nucleus and activates transcription of microRNA (miR)-17 and miR-19a, which bind to and prevent translation of TNF-α and TLR7 messenger RNAs (mRNAs). This phenomenon can be prevented by the use of IL-6 receptor blocking antibodies (ie, ACTEMRA) or JAK inhibitors (ie, ruxolitinib). Professional illustration by Patrick Lane, ScEYEnce Studios.