Downregulation of monocyte chemoattractant protein-1 involving short interfering RNA attenuates hapten-induced contact hypersensitivity.
Contact hypersensitivity (CHS) is a common skin disease, presenting clinically as allergic contact dermatitis. At inflammatory sites in a typical CHS model in the mouse ear, elevated expression of monocyte chemoattractant protein-1 (MCP-1) has been reported. MCP-1 is a potent chemotactic factor for many types of leukocytes including monocytes/macrophages and T cells. In this study, we aimed at developing a therapy for CHS involving RNA interference targeting MCP-1. A short interfering RNA (siRNA) to mouse MCP-1 successfully inhibited the secretion of MCP-1 by a fibroblastic cell line, L929, and RAW 264.7 cells derived from macrophages, and strikingly suppressed ear swelling in a CHS model. The siRNA systemically administered inhibited the infiltration of both monocytes/macrophages and T cells in the CHS model. Atelocollagen was used in this therapy as a delivery reagent for siRNA into the animal body. Atelocollagen facilitated the incorporation of the siRNA into macrophages/monocytes and fibroblasts, which vigorously secrete MCP-1 protein at inflammatory sites in CHS. This therapy had no adverse effects such as induction of interferon, or liver or renal damage. Our data indicate that the systemic delivery of siRNA targeting MCP-1 is a potent therapeutic strategy for CHS treatment.
Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Takuji
T
Ishimoto
Yoshifumi
Y
Takei
Yukio
Y
Yuzawa
Koji
K
Hanai
Shunji
S
Nagahara
Yuzo
Y
Tarumi
Seiichi
S
Matsuo
Kenji
K
Kadomatsu
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D003877:Dermatitis, Contact / Q000209:etiology / Q000235:genetics / Q000628:therapy*; D004139:Dinitrofluorobenzene; D004423:Ear / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006241:Haptens; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000628:therapy; D008081:Liposomes / Q000737:chemistry; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014162:Transfection
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D006241:Haptens; D008081:Liposomes; D034741:RNA, Small Interfering; C059821:atelocollagen; D003094:Collagen; D004139:Dinitrofluorobenzene