Free IL-15 Is More Abundant Than IL-15 Complexed With Soluble IL-15 Receptor-α in Murine Serum: Implications for the Mechanism of IL-15 Secretion

IL-15 is a cytokine that is part of the innate immune system, as well as a proposed myokine released from skeletal muscle during physical exercise that mediates many of the positive physiological effects of exercise. Many of the immune functions of IL-15 are mediated by juxtacrine signaling via externalized IL-15 bound to membrane-associated IL-15 receptor-alpha (IL-15R alpha). Serum and plasma samples also contain measurable concentrations of IL-15, believed to arise from proteolytic cleavage of membrane-associated IL-15/IL-15R alpha complexes to generate soluble IL-15/IL-15R alpha species. Here, we validate commercial assays that can distinguish the free form of IL-15 and IL-15/IL-15R alpha complexes. These assays showed that most (86%) IL-15 in mouse serum resides in the free state, with a minor proportion (14%) residing in complex with IL-15R alpha. Given the much shorter half-life of free IL-15 compared with IL-15/IL-15R alpha complexes, these findings cast doubt on the currently accepted model for IL-15 secretion from cleavage of membrane-bound IL-15/IL-15R alpha and suggest that IL-15 is released as a free molecule by an unknown mechanism.