Dermal fibroblasts sustain proliferation of activated T cells via membrane-bound interleukin-15 upon long-term stimulation with tumor necrosis factor-alpha.
In chronic inflammatory conditions, mononuclear cells infiltrate the connective tissue attracted by fibroblast-secreted chemokines. The role of fibroblasts in sustaining the lymphocyte immune response upon cellular infiltration is so far unresolved. We here report that, upon prolonged stimulation with tumor necrosis factor-alpha, dermal fibroblasts enhance proliferation of activated T cells whereas unstimulated fibroblasts do not. T cell growth stimulation requires cell contact of tumor necrosis factor-alpha stimulated fibroblasts to T cells and is not due to soluble factors. Growth stimulation is substantially blocked by neutralizing antibodies to interleukin-15. Fluorescence-activated cell sorter analyses revealed that tumor necrosis factor alpha stimulated fibroblasts expose interleukin-15 in a membrane-bound form on the cell surface whereas nonstimulated fibroblasts and interferon-gamma treated fibroblasts do not. The amount of membrane interleukin-15 increases with the duration of tumor necrosis factor-alpha stimulation for at least 3 d. Unstimulated fibroblasts, however, accumulate interleukin-15 in the cytoplasm. No interleukin-15 could be detected in the culture supernatant. Immunohistochemical analyses confirmed membrane interleukin-15 on dermal fibroblasts in discoid lupus erythematosus skin lesions whereas no membrane interleukin-15 was found on the surface of fibroblasts in healthy skin. We conclude that dermal fibroblasts upon long-term tumor necrosis factor-alpha stimulation during chronic inflammation are involved via membrane-bound interleukin-15 in stimulating proliferation of accumulated, activated T cells.
Rappl
G
G
Department of Dermatology, The Saarland University Hospital, Homburg/Saar, Germany.
Kapsokefalou
A
A
Heuser
C
C
Rössler
M
M
Ugurel
S
S
Tilgen
W
W
Reinhold
U
U
Abken
H
H
D000906:Antibodies; D002455:Cell Division / Q000502:physiology; D002462:Cell Membrane / Q000737:chemistry; D005347:Fibroblasts / Q000166:cytology*; D006801:Humans; D007124:Immunoenzyme Techniques; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D008179:Lupus Erythematosus, Discoid / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000166:cytology*; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000906:Antibodies; D019409:Interleukin-15; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha