Downregulation of Monocyte Chemoattractant Protein-1 Involving Short Interfering RNA Attenuates Hapten-induced Contact Hypersensitivity

Abstract

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.

Systemic delivery of siRNA specific to tumor mediated by atelocollagen: Combined therapy using siRNA targeting Bcl‐xL and cisplatin against prostate cancer

“…43 Moreover, we also successfully enabled the delivery of siRNA with atelocollagen intravenously to inflammatory tissues via a similar EPR effect. 16 In the inflammatory tissues, MCP-1 upregulates the permeability. 16,44,45 From a viewpoint of enhanced permeability, tumors and inflammatory tissues resemble each other.…”

“…16 In the inflammatory tissues, MCP-1 upregulates the permeability. 16,44,45 From a viewpoint of enhanced permeability, tumors and inflammatory tissues resemble each other. Therefore, the atelocollagenmediated systemic method enables to deliver the siRNA specifically into either tumors or inflammatory tissues.…”

“…For preparing the siRNA/atelocollagen complex, equal volumes of atelocollagen in PBS and siRNA solution were mixed by rotating for 20 min at 4°C. 14,16 siRNA transfection in vitro…”

“…We and Ochiya's group previously showed the efficacy of atelocollagen for delivering nucleic acid compounds such as antisense oligodeoxynucleotides, [10][11][12] morpholino antisense oligomers, 13 and siRNAs, [14][15][16] especially in vivo. Atelocollagen, which is prepared from bovine dermis, 17,18 contributes to increases in cellular uptake, nuclease resistance and the prolonged release of siRNA, 14,[19][20][21] as well as plasmid DNA, 17 and antisense oligonucleotide compounds, 10,11,13,22 administered to tumors.…”

“…23 More recently, we also successfully showed a therapeutic effect on inflammatory disease via atelocollagen-mediated systemic administration of siRNA targeting monocyte chemoattractant protein-1 (MCP-1). 16 However, little information is available about treating pregrown xenografted solid tumors by this modality, i.e., adequate dose, frequency and interval of siRNA injections, although there is a lot of information about local injection to treat tumors.…”