Abstract

Midkine (MK), a heparin-binding growth factor, reportedly contributes to inflammatory diseases, including Crohn's disease and rheumatoid arthritis. We previously showed that MK aggravates experimental autoimmune encephalomyelitis (EAE) by decreasing regulatory CD4(+)CD25(+)Foxp3(+) T cells (Tregs), a population that regulates the development of autoimmune responses, although the precise mechanism remains uncertain. In this article, we show that MK produced in inflammatory conditions suppresses the development of tolerogenic dendritic cells (DCregs), which drive the development of inducible Treg. MK suppressed DCreg-mediated expansion of the CD4(+)CD25(+)Foxp3(+) Treg population. DCregs expressed significantly higher levels of CD45RB and produced significantly less IL-12 compared with conventional dendritic cells. However, MK downregulated CD45RB expression and induced IL-12 production by reducing phosphorylated STAT3 levels via src homology region 2 domain-containing phosphatase-2 in DCreg. Inhibiting MK activity with anti-MK RNA aptamers, which bind to the targeted protein to suppress the function of the protein, increased the numbers of CD11c(low)CD45RB(+) dendritic cells and Tregs in the draining lymph nodes and suppressed the severity of EAE, an animal model of multiple sclerosis. Our results also demonstrated that MK was produced by inflammatory cells, in particular, CD4(+) T cells under inflammatory conditions. Taken together, these results suggest that MK aggravates EAE by suppressing DCreg development, thereby impairing the Treg population. Thus, MK is a promising therapeutic target for various autoimmune diseases.

Links

Publisher Full Text

Authors

Sonobe Y, Li H, Jin S, Kishida S, Kadomatsu K, Takeuchi H, Mizuno T, Suzumura A

Institution

Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan. sonobe@riem.nagoya-u.ac.jp

Source

Journal of immunology (Baltimore, Md. : 1950) 188:6 2012 Mar 15 pg 2602-11

MeSH

Adoptive Transfer
Animals
Blotting, Western
Cell Differentiation
Cell Separation
Dendritic Cells
Encephalomyelitis, Autoimmune, Experimental
Enzyme-Linked Immunosorbent Assay
Female
Flow Cytometry
Immune Tolerance
Lymphocyte Activation
Lymphocyte Culture Test, Mixed
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
T-Lymphocytes, Regulatory

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22323540