IL-6 exerts its pleiotropic activities on its target cells via the IL-6 alpha-receptor (IL-6R), which is expressed on a limited number of cell types. IL-6 can further signal via soluble forms of its receptor (sIL6R), a process that has been termed trans-signaling. Recently, CD5 was described as an alternative alpha receptor for IL-6 on B cells leading to the phosphorylation of the transcription factor STAT3 via the signal-transducing 13-receptor gp130 in a Jak2-dependent manner. In this study, we sought to investigate whether IL-6 was also able to signal via soluble CD5 (sCD5) analogous to IL-6 trans-signaling. We show that 1L-6 indeed binds to sCD5, but that this does not lead to the activation of signal transduction or cell proliferation. Furthermore, sCD5 did also not interfere with IL-6 classic signaling, suggesting that the affinity between the two proteins was too weak to provoke a biological effect. Thus, trans-signaling of IL- 6 can only occur via sIL-6R, but not sCD5. (C) 2017 Elsevier Inc. All rights reserved.