Dual TNF-α/IL-12p40 Interference as a Strategy to Protect Against Colitis Based on miR-16 Precursors With Macrophage Targeting Vectors.

Abstract

Cytokines are central components of the mucosal inflammatory responses that take place during the development of Crohn's disease. Cell-specific combination therapies against cytokines may lead to increased efficacy and even reduced side effects. Therefore, a colonic macrophage-specific therapy using miR-16 precursors that can target both TNF-α and IL-12p40 was tested for its efficacy in experimental colitic mice. Galactosylated low molecular weight chitosan (G-LMWC) associated with miR-16 precursors were intracolonically injected into mice. The cellular localization of miR-16 precursors was determined. The therapeutic effects and possible mechanism were further studied in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitic mice. The results show that specific upregulation of miR-16 level in colonic macrophages significantly reduces TNF-α and IL-12p40 expression, which could suppress the associated mucosal inflammation and ultimately result in the relief of colitic symptoms. This strategy, based on the dual silencing of colonic macrophage-specific cytokines, represents a potential therapeutic approach that may be valuable for colitis therapy.

• Authors: Zhen Huang, Junting Ma, Mengjie Chen, Haoyang Jiang, Yong Fu, Jingjing Gan, Lei Dong, Junfeng Zhang, Jiangning Chen
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 23 Issue 10 Pg. 1611-21 (Oct 2015) ISSN: 1525-0024 [Electronic] United States
• PMID: 26073885 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Interleukin-12 Subunit p40
• MicroRNAs
• Mirn16 microRNA, mouse
• RNA Precursors
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Base Sequence
• Binding Sites
• Colitis (etiology, metabolism, mortality, pathology)
• Cytokines (metabolism)
• Disease Models, Animal
• Gene Expression Regulation
• Interleukin-12 Subunit p40 (genetics, metabolism)
• Intestinal Mucosa (immunology, metabolism, pathology)
• Macrophages (immunology, metabolism)
• Macrophages, Peritoneal (immunology, metabolism)
• Mice
• MicroRNAs (genetics)
• RNA Interference
• RNA Precursors (genetics)
• Tumor Necrosis Factor-alpha (genetics, metabolism)