Human mast cells stimulate fibroblast proliferation, collagen synthesis and lattice contraction: a direct role for mast cells in skin fibrosis.
BACKGROUND
Mast cells, the key cells of immediate hypersensitivity type reactions, have also been postulated to have a central role in influencing tissue remodelling and fibrosis occurring in the skin.


OBJECTIVE
Our aim was to investigate the direct role of human mast cells (HMC) in skin fibrotic processes, by assessing the effects of the addition of the human mast cell line HMC-1 to human skin fibroblasts, and to identify the responsible mediators.


METHODS
HMC-1 sonicates were added to human skin fibroblasts and the following parameters were evaluated: proliferation ([3H]-thymidine), collagen synthesis ([3H] proline), activity of matrix metalloproteinases (MMPs) (zymography) and tissue inhibitors of metalloproteinases (TIMPs) (reverse zymography), and collagen gel contraction.


RESULTS
HMC-1 sonicate increased significantly both proliferation and collagen production in the human skin fibroblasts and these properties were not affected by heating of the sonicate (56 degrees C, 30 min, or 100 degrees C, 3 min). Two main mast cell mediators, histamine and tryptase, were found to be responsible for the increase in fibroblast proliferation and collagen production. HMC-1 sonicate did not display any pre-formed gelatinase activity, and its addition to the fibroblasts did not change their pro-MMP-2 and MMP-2 activity. On the other hand, HMC-1 were found to possess TIMP-1 and TIMP-2. Addition of HMC-1 had no effect on fibroblasts TIMP-1 but induced a dose-dependent increase of TIMP-2 activity. In addition, HMC-1 sonicate seeded together with the fibroblasts in tri-dimensional collagen gel significantly enhanced their contraction.


CONCLUSIONS
We have shown that human mast cells, by granule-stored and therefore quickly releasable mediators, increase human skin fibroblast proliferation, collagen synthesis, TIMP-2 and collagen gel contraction. Therefore, mast cells have a direct and potentiating role in skin remodelling and fibrosis.
Garbuzenko
E
E
Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University-Hadassah Medical School, PO 12065, Jerusalem 91120, Israel.
Nagler
A
A
Pickholtz
D
D
Gillery
P
P
Reich
R
R
Maquart
F-X
FX
Levi-Schaffer
F
F
D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D003094:Collagen / Q000096:biosynthesis*; D005347:Fibroblasts / Q000166:cytology*; D005355:Fibrosis / Q000503:physiopathology; D006632:Histamine / Q000502:physiology; D006801:Humans; D008407:Mast Cells / Q000502:physiology*; D012697:Serine Endopeptidases / Q000502:physiology; D012867:Skin / Q000473:pathology / Q000503:physiopathology; D013010:Sonication; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D053802:Tryptases; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D019716:Tissue Inhibitor of Metalloproteinase-2; D006632:Histamine; D003094:Collagen; D012697:Serine Endopeptidases; D053802:Tryptases