Inhibition of midkine alleviates experimental autoimmune encephalomyelitis through the expansion of regulatory T cell population

Wang, Jinyan; Takeuchi, Hideyuki; Sonobe, Yoshifumi; Jin, Shijie; Mizuno, Tetsuya; Miyakawa, Shin; Fujiwara, Masatoshi; Nakamura, Yoshikazu; Kato, Takuma; Muramatsu, Hisako; Muramatsu, Takashi; Suzumura, Akio

doi:10.1073/pnas.0709592105

Cited by 111 publications

(160 citation statements)

References 51 publications

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“…Recently, midkine was found to act as a suppressor of T regulatory lymphocytes (Treg) (31), the dysfunction of which contributes to immune abnormalities of mucosa (33,34). Wang et al (31) demonstrated that attenuated symptoms of encephalomyelitis in midkine-deficient animals resulted from increased Treg cell population. Midkine was found to decrease cell number in a dose-dependent manner, whereas the administration of anti-midkine RNA aptamers expanded the Treg cell population.…”

Section: Discussionmentioning

confidence: 99%

“…It may play a role in recruitment of neutrophils and macrophages into inflamed tissue (23,24), and up-regulation of synthesis of inflammatory mediators (25)(26)(27). Animal studies have revealed that several inflammation-related phenomena were substantially alleviated in midkine-deficient animals (12,25,(28)(29)(30)(31)(32). The mechanisms mentioned above may also operate in the involvement of midkine in the pathogenesis of UC since the accumulation of neutrophiles and monocytes associated with aberrant inflammatory response is essential for development of UC (14).…”

Section: Discussionmentioning

confidence: 99%

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Clinical relevance of circulating midkine in ulcerative colitis

Krzystek−Korpacka

Neubauer

Matusiewicz

2009

Clinical Chemistry and Laboratory Medicine

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Background: Non-invasive biochemical markers are needed to support the diagnosis of ulcerative colitis (UC), an incurable disease of unknown pathology. Midkine is an angiogenic cytokine, chemotactic towards neutrophils and macrophages, and a T-regulatory cell suppressor. Methods: Serum midkine was measured immunoenzymatically in 93 UC patients and 108 healthy subjects, and evaluated with respect to disease status, endoscopic, inflammatory and angiogenic activity. The diagnostic value of midkine was compared to Creactive protein (CRP) using receiver operating characteristics (ROC) analysis. Results: Midkine was higher (p-0.0001) in inactive (199 ng/L) and active UC (351 ng/L) compared with controls (93 ng/L), and reflected disease activity (rs0.427, p-0.001). Midkine was correlated with CRP, erythrocyte sedimentation rate (ESR), leukocytes, platelets, interleukin-6, paraoxonase-1, albumin, transferrin, iron, hemoglobin, and hematocrit. Midkine correlated with angiogenic factors: vascular endothelial growth factor-A and platelet-derived growth factor-BB. As a marker of UC, midkine showed a diagnostic accuracy of 85%, sensitivity of 72%, specificity of 82%, whereas CRP showed 83%, 65% and 91%, respectively. As a marker of active UC, midkine showed a diagnostic accuracy of 87%, sensitivity of 84%, specificity of 75%, whereas CRP showed 75%, 63% and 83%, respectively. Combined assessment of midkine and CRP improved sensitivity but substantially decreased specificity. Conclusions: UC is associated with increased circulating midkine, which corresponds with clinical, endoscopic, inflammatory and angiogenic activity, and anemia. Performance of midkine as a marker of UC or active UC was comparable to that of CRP. Clin Chem Lab Med 2009;47:1085-90.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical relevance of circulating midkine in ulcerative colitis

Krzystek−Korpacka

Neubauer

Matusiewicz

2009

Clinical Chemistry and Laboratory Medicine

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“…The mouse primers used are shown in Supplemental Table I. cells/well) were cultured with mitomycin C-treated feeder cells (5 3 10 5 cells/well) in SHED-CM or DMEM in the presence of MOG 35-55 (20 ng/ml) for 72 h. The supernatants were collected for cytokine analysis, and the cells were analyzed using a BrdU cell proliferation assay (Calbiochem, San Diego, CA). The concentrations of IL-17, IFN-g, and IL-2 were assessed using the corresponding cytokine-specific ELISA kits (IL-17, IFN-g, R&D Systems; IL-2, BD Biosciences, Franklin Lakes, NJ), as described previously (24,25). Six independent assays were performed.…”

Section: Rna Extraction and Rt-pcrmentioning

confidence: 99%

“…C57BL/6J mice were purchased from Japan SLC (Hamamatsu, Japan). EAE was induced as described previously (24,25). Briefly, 8-wk-old female C57BL/6J mice were immunized s.c. at the base of the tail with 0.2 ml an emulsion containing 200 mg myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 (MOG ; MEVG-WYRSPFSRVVHLYRNGK; Operon Biotechnologies, Tokyo, Japan) in saline combined with an equal volume of CFA (Sigma-Aldrich, St. Louis, MO) containing 300 ml heat-killed Mycobacterium tuberculosis H37Ra (Difco, Detroit, MI).…”

Section: Eae Micementioning

confidence: 99%

Conditioned Medium from the Stem Cells of Human Exfoliated Deciduous Teeth Ameliorates Experimental Autoimmune Encephalomyelitis

Shimojima

Takeuchi

Jin

et al. 2016

The Journal of Immunology

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Multiple sclerosis (MS) is a major neuroinflammatory demyelinating disease of the CNS. Current MS treatments, including immunomodulators and immunosuppressants, do not result in complete remission. Stem cells from human exfoliated deciduous teeth (SHEDs) are mesenchymal stem cells derived from dental pulp. Both SHED and SHED-conditioned medium (SHED-CM) exhibit immunomodulatory and regenerative activities and have the potential to treat various diseases. In this study, we investigated the efficacy of SHED-CM in treating experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. EAE mice treated with a single injection of SHED-CM exhibited significantly improved disease scores, reduced demyelination and axonal injury, and reduced inflammatory cell infiltration and proinflammatory cytokine expression in the spinal cord, which was associated with a shift in the microglia/macrophage phenotype from M1 to M2. SHED-CM also inhibited the proliferation of myelin oligodendrocyte glycoprotein–specific CD4+ T cells, as well as their production of proinflammatory cytokines in vitro. Treatment of EAE mice with the secreted ectodomain of sialic acid–binding Ig-like lectin-9, a major component of SHED-CM, recapitulated the effects of SHED-CM treatment. Our data suggest that SHED-CM and secreted ectodomain of sialic acid–binding Ig-like lectin-9 may be novel therapeutic treatments for autoimmune diseases, such as MS.

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“…CNS cells were prepared as previously described (22). Briefly, mice were intracardially perfused with PBS through the left ventricle.…”

Section: Isolation Of Cns Mononuclear Cellsmentioning

confidence: 99%

IL-9 Promotes Th17 Cell Migration into the Central Nervous System via CC Chemokine Ligand-20 Produced by Astrocytes

Zhou

Sonobe

Akahori

et al. 2011

The Journal of Immunology

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129

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Newly discovered IL-9–producing helper T cells (Th9) reportedly exert both aggravating and suppressive roles on experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. However, it is still unclear whether Th9 is a distinct Th cell subset and how IL-9 functions in the CNS. In this study, we show that IL-9 is produced by naive CD4+ T cells that were stimulated with anti-CD3 and anti-CD28 Abs under the conditions of Th2-, inducible regulatory T cell-, Th17-, and Th9-polarizing conditions and that IL-9 production is significantly suppressed in the absence of IL-4, suggesting that IL-4 is critical for the induction of IL-9 by each producing cell. The IL-9 receptor complex, IL-9R and IL-2Rγ, is constitutively expressed on astrocytes. IL-9 induces astrocytes to produce CCL-20 but not other chemokines, including CCL-2, CCL-3, and CXCL-2 by astrocytes. The conditioned medium of IL-9–stimulated astrocytes induces Th17 cell migration in vitro, which is cancelled by adding anti–CCL-20 neutralizing Abs. Treating with anti–IL-9 neutralizing Abs attenuates experimental autoimmune encephalomyelitis, decreases the number of infiltrating Th17 cells, and reduces CCL-20 expression in astrocytes. These results suggest that IL-9 is produced by several Th cell subsets in the presence of IL-4 and induces CCL-20 production by astrocytes to induce the migration of Th17 cells into the CNS.

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Inhibition of midkine alleviates experimental autoimmune encephalomyelitis through the expansion of regulatory T cell population

Cited by 111 publications

References 51 publications

Clinical relevance of circulating midkine in ulcerative colitis

Clinical relevance of circulating midkine in ulcerative colitis

Conditioned Medium from the Stem Cells of Human Exfoliated Deciduous Teeth Ameliorates Experimental Autoimmune Encephalomyelitis

IL-9 Promotes Th17 Cell Migration into the Central Nervous System via CC Chemokine Ligand-20 Produced by Astrocytes

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