Systemic leukocyte-directed siRNA delivery revealing cyclin D1 as an anti-inflammatory target.
Cyclin D1 (CyD1) is a pivotal cell cycle-regulatory molecule and a well-studied therapeutic target for cancer. Although CyD1 is also strongly up-regulated at sites of inflammation, its exact roles in this context remain uncharacterized. To address this question, we developed a strategy for selectively silencing CyD1 in leukocytes in vivo. Targeted stabilized nanoparticles (tsNPs) were loaded with CyD1-small interfering RNA (siRNA). Antibodies to beta(7) integrin (beta(7) I) were then used to target specific leukocyte subsets involved in gut inflammation. Systemic application of beta(7) I-tsNPs silenced CyD1 in leukocytes and reversed experimentally induced colitis in mice by suppressing leukocyte proliferation and T helper cell 1 cytokine expression. This study reveals CyD1 to be a potential anti-inflammatory target, and suggests that the application of similar modes of targeting by siRNA may be feasible in other therapeutic settings.
Peer
Dan
D
Immune Disease Institute and Department of Anesthesia, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Park
Eun Jeong
EJ
Morishita
Yoshiyuki
Y
Carman
Christopher V
CV
Shimaoka
Motomu
M
D000818:Animals; D000906:Antibodies; D049109:Cell Proliferation; D003092:Colitis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000473:pathology; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics* / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D004337:Drug Carriers; D019940:Genes, bcl-1; D006820:Hyaluronic Acid; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D039641:Integrin beta Chains / Q000276:immunology; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008081:Liposomes; D051379:Mice; D053758:Nanoparticles; D011479:Protamines; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
D000906:Antibodies; D056741:Cyclin D; D016213:Cyclins; D016207:Cytokines; D004337:Drug Carriers; D039641:Integrin beta Chains; D008081:Liposomes; D011479:Protamines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C091368:integrin beta7; D006820:Hyaluronic Acid