The angiogenesis inhibitor thrombospondin-1 inhibits acute cutaneous hypersensitivity reactions.
There is increasing evidence that vascular remodeling and endothelial cell activation promote acute and chronic inflammation. Thrombospondin 1 (TSP-1) is a potent endogenous angiogenesis inhibitor thought to play an important role in maintaining cutaneous vascular quiescence. We first investigated TSP-1 expression in human and contact hypersensitivity (CHS) reactions and found that TSP-1 was upregulated in the inflamed skin of patients and in mice. To elucidate the function of TSP-1 in cutaneous inflammation, we induced CHS reactions in the skin of mice with targeted epidermal TSP-1 overexpression in TSP-1-deficient mice and in wild-type mice. We found decreased edema formation, angiogenesis, and inflammatory infiltrate in the inflamed skin of TSP-1 transgenic mice. Conversely, TSP-1-deficient mice exhibited an enhanced and prolonged inflammation, characterized by increased edema formation, enhanced vascular remodeling, and increased neutrophilic infiltrate, when compared with wild-type mice. Moreover, we found strong upregulation of the proinflammatory cytokines IL-1beta, macrophage inflammatory protein 2, and tumor necrosis factor-alpha in the inflamed skin of TSP-1-deficient mice. Our results indicate that TSP-1 downregulates cutaneous delayed-type hypersensitivity reactions by acting on several distinct pathways mediating skin inflammation.
Velasco
Paula
P
Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Huegel
Rainer
R
Brasch
Jochen
J
Schröder
Jens M
JM
Weichenthal
Michael
M
Stockfleth
Eggert
E
Schwarz
Thomas
T
Lawler
Jack
J
Detmar
Michael
M
Lange-Asschenfeldt
Bernhard
B
D000208:Acute Disease; D020533:Angiogenesis Inhibitors / Q000502:physiology*; D000818:Animals; D018955:CD36 Antigens / Q000032:analysis; D054426:Chemokine CXCL2 / Q000096:biosynthesis; D017449:Dermatitis, Allergic Contact / Q000517:prevention & control*; D004487:Edema / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000502:physiology; D012867:Skin / Q000378:metabolism; D019700:Thrombospondin 1 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D020533:Angiogenesis Inhibitors; D018955:CD36 Antigens; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D053583:Interleukin-1beta; D019700:Thrombospondin 1; D014409:Tumor Necrosis Factor-alpha