Intracellular IL-15 controls mast cell survival.
The regulation of mast cell activities and survival is a central issue in inflammatory immune responses. Here, we have investigated the role of mouse interleukin-15, a pro-inflammatory and pleiotropic cytokine, in the control of mast cell survival and homeostasis. We report that aged IL-15-/- mice show a reduced number of peritoneal mast cells compared to WT mice. Furthermore, IL-15 deficiency in bone marrow derived mouse mast cells (BMMCs) results in increased susceptibility to apoptosis mediated by growth factor deprivation and A-SMase-treatment. IL-15-/- BMMCs show a constitutive stronger mRNA and protein expression as well as enzymatic activity of the members of the mitochondrial apoptotic pathways including acidic lysosomal aspartate protease cathepsin D (CTSD), endogenous acid sphingomyelinase (A-SMase), caspase-3 and -7 compared to wild type (WT) BMMCs. Furthermore, IL-15-/- BMMCs constitutively generate more A-SMase-derived ceramide than WT controls and display a decreased expression of pro-survival sphingosin-1-phosphate (SPP) both in cytosol and membrane cell fractions. Furthermore, pre-treatment of mast cells with imipramine or pepstatin A, inhibitors of the intracellular acid sphingomyelinase and cathepsin D pathways respectively, increases survival in IL-15-/- BMMCs. These findings suggest that intracellular IL-15 is a key regulator of pathways controlling primary mouse mast cell homeostasis.
Mirghomizadeh
Farhad
F
Department of Immunology and Cell Biology, Research Center Borstel, Parkallee 22, D-23845 Borstel, Germany.
Winoto-Morbach
Supandi
S
Orinska
Zane
Z
Lee
Kyeong-Hee
KH
Schütze
Stefan
S
Bulfone-Paus
Silvia
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000502:physiology*; D002518:Ceramides / Q000378:metabolism; D006133:Growth Substances / Q000494:pharmacology / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D019409:Interleukin-15 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008407:Mast Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics
D002518:Ceramides; D006133:Growth Substances; D019409:Interleukin-15; D012333:RNA, Messenger