Reverse Signaling through Membrane-bound Interleukin-15

• Published in: The Journal of biological chemistry 2004-10, Vol.279 (40), p.42192-42201
• Main Authors: Budagian, Vadim, Bulanova, Elena, Orinska, Zane, Pohl, Thomas, Borden, Ernest C, Silverman, Robert, Bulfone-Paus, Silvia
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Cell Movement; Cells, Cultured; Cytokines - biosynthesis; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Humans; Immunity, Cellular; Interferon-gamma - pharmacology; Interleukin-15 - physiology; Ligands; Male; Membrane Proteins - physiology; Mitogen-Activated Protein Kinases - metabolism; Monocytes; Prostatic Neoplasms - pathology; Protein-Tyrosine Kinases - metabolism; Receptors, Interleukin-15; Receptors, Interleukin-2; Signal Transduction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M403182200

The results from this study implicate membrane-anchored interleukin (IL)-15 constitutively expressed on the cell surface of PC-3 human prostate carcinoma cells and interferon-γ-activated human monocytes in reverse signaling upon stimulation with soluble IL-15 receptor-α or anti-IL-15 antibodies, mediating the outside-to-inside signal transduction that involves the activation of members of the MAPK family (ERK and p38) and focal adhesion kinase. The presence of membrane-bound IL-15 was not dependent on the expression of the trimeric IL-15 receptor complex by these cells and resisted treatment with acidic buffer or trypsin. Reverse signaling through membrane-bound IL-15 considerably increased the production of several pro-inflammatory cytokines by monocytes, such as IL-6, IL-8, and tumor necrosis factor-α, thereby indicating the relevance of this process to the complex immunomodulatory function of these cells. Furthermore, stimulation of transmembrane IL-15 also enhanced the transcription of IL-6 and IL-8 in the PC-3 cell line and promoted migration of PC-3 cells as well as LNCaP human prostate carcinoma cells stably expressing IL-15 on the cell surface. Thus, IL-15 can exist as a biologically active transmembrane molecule that possesses dual ligand-receptor qualities with a potential to induce bidirectional signaling. This fact highlights a new level of complexity in the biology of IL-15 and offers novel important insights into our understanding of the cellular responses modulated by this pleiotropic cytokine.