Immunological aspects of REIC/Dkk-3 in monocyte differentiation and tumor regression.
The REIC/Dkk-3 gene has been reported to be a tumor suppressor and the expression is significantly down-regulated in a broad range of cancer cell types. The protein is secretory, but the physiological function remains unclear. This study demonstrated that recombinant REIC/Dkk-3 protein induced the differentiation of human CD14+ monocytes into a novel cell type (REIC/Dkk-3Mo). REIC/Dkk-3Mo resembles immature dendritic cells generated with IL-4 and GM-CSF. Both these cell populations exhibit similar proportions of CD11c+, CD40+, CD86+ and HLA-DR+ cells and endocytic capacity, but REIC/Dkk-3Mo is negative for CD1a antigen. An analysis of the signal transducers and activators of transcription (STAT) pathways revealed that REIC/Dkk-3 induces phosphorylation of STAT 1 and STAT 3. Furthermore, intratumoral administration of REIC/Dkk-3 protein significantly suppressed tumor growth with CD11c+ and CD8+ (dendritic and killer T cell marker, respectively) cell accumulation and enhanced anti-cancer cytolytic activity of splenocytes. These data indicated a cytokine-like role of REIC/Dkk-3 protein in monocyte differentiation that might be exploited therapeutically.
Watanabe
Masami
M
Innovation Center Okayama for Nanobio-Targeted Therapy, Okayama University, Okayama 700-8558, Japan. mwcorrespondence@gmail.com
Kashiwakura
Yuji
Y
Huang
Peng
P
Ochiai
Kazuhiko
K
Futami
Junichiro
J
Li
Shun-Ai
SA
Takaoka
Munenori
M
Nasu
Yasutomo
Y
Sakaguchi
Masakiyo
M
Huh
Nam-Ho
NH
Kumon
Hiromi
H
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016466:CHO Cells; D002455:Cell Division / Q000276:immunology*; D045744:Cell Line, Tumor; D018925:Chemokines; D006224:Cricetinae; D003412:Cricetulus; D003713:Dendritic Cells / Q000276:immunology*; D018450:Disease Progression; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology*; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008297:Male; D051379:Mice; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins