Reverse signaling through membrane-bound interleukin-15.
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-gamma-activated human monocytes in reverse signaling upon stimulation with soluble IL-15 receptor-alpha 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-alpha, 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.
Department of Immunology and Cell Biology, Research Center Borstel, D-23845 Borstel, Germany.
Vadim
V
Budagian
Elena
E
Bulanova
Zane
Z
Orinska
Thomas
T
Pohl
Ernest C
EC
Borden
Robert
R
Silverman
Silvia
S
Bulfone-Paus
D045744:Cell Line, Tumor; D002465:Cell Movement; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000494:pharmacology; D019409:Interleukin-15 / Q000502:physiology*; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes; D011471:Prostatic Neoplasms / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D015398:Signal Transduction
D016207:Cytokines; C508024:IL15RA protein, human; D019409:Interleukin-15; D008024:Ligands; D008565:Membrane Proteins; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D020928:Mitogen-Activated Protein Kinases