Objective To fully understand why C-reactive protein (CRP) is usually only mildly elevated in active systemic lupus erythematosus (SLE), although interleukin-6 (IL-6) is increased, but is high in SLE patients with bacterial infections. Methods Sera and peripheral blood mononuclear cells (PBMCs) of SLE patients and healthy individuals were investigated. IL-6 and soluble IL-6 receptor (sIL-6R) were measured by ELISA. Membrane IL-6 receptor-α (CD126), gp130 (CD130) and signal transducer and activator of transcription 3 (STAT3) phosphorylation after IL-6 stimulation were analysed by flow cytometry. PBMCs and HepG2 liver cells were stimulated with various cytokines, and IL-6 receptor shedding was determined by immunoprecipitation and western blotting of supernatants. HEK-293 T cells were transfected with wild type CD126 or a shedding-resistant mutant, and soluble sIL-6R was measured following cytokine stimulation. Results While sIL-6R and IL-6 were increased with SLE activity, CD126 positive lymphocytes were decreased in SLE. IL-6 plus IFNα decreased CD126 on lymphocytes, but increased sIL-6R in their supernatant, detected by immunoprecipitation and western blotting. IL-6 plus IFNα on HepG2 liver cells resulted in a similar sIL-6R increase. Increased supernatant sIL-6R was seen in HEK-293 T cells transfected with wild type CD126, but not those transfected with the shedding-resistant mutant. STAT3 phosphorylation upon IL-6 stimulation was reduced. Conclusion The combination of IL-6 and type I IFN induces shedding of CD126 to sIL-6R, shifting IL-6 signalling to trans-signalling. In situations of IL-6 excess over sIL-6R only, IL-6 or IL-6-sIL-6R complexes reach the liver and increase CRP. These findings not only explain the discrepancy in SLE, but also have implications for severe viral infection.