Midkine as a regulator of <scp>B</scp> cell survival in health and disease

Cohen, Sivan; Shachar, Idit

doi:10.1111/bph.12419

Cited by 13 publications

(9 citation statements)

References 89 publications

(120 reference statements)

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“…In addition, MK has also been demonstrated to serve as a regulator of mature B-cell survival in B-cell lymphoma. 48 In the present study, Mdk À/À mice did not show any immune-complex deposition in subepithelial areas, which was previously reported. 49 MK may affect humoral immunity through activation of T cells in TMPD-induced LN.…”

Section: Discussionsupporting

confidence: 86%

Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis

Masuda

Maeda

Sato

et al. 2017

The American Journal of Pathology

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Activated T cells play crucial roles in the pathogenesis of autoimmune diseases, including lupus nephritis (LN). The activation of calcineurin/nuclear factor of activated T cells (NFAT) and STAT4 signaling is essential for T cells to perform various effector functions. Here, we identified the growth factor midkine (MK; gene name, Mdk) as a novel regulator in the pathogenesis of 2,6,10,14-tetramethylpentadecane-induced LN via activation of NFAT and IL-12/STAT4 signaling. Wild-type (Mdk) mice showed more severe glomerular injury than MK-deficient (Mdk) mice, as demonstrated by mesangial hypercellularity and matrix expansion, and glomerular capillary loops with immune-complex deposition. Compared with Mdk mice, the frequency of splenic CD69 T cells and T helper (Th) 1 cells, but not of regulatory T cells, was augmented in Mdk mice in proportion to LN disease activity, and was accompanied by skewed cytokine production. MK expression was also enhanced in activated CD4 T cells in vivo and in vitro. MK induced activated CD4 T cells expressing CD69 through nuclear activation of NFAT transcription and selectively increased in vitro differentiation of naive CD4 T cells into Th1 cells by promoting IL-12/STAT4 signaling. These results suggest that MK serves an indispensable role in the NFAT-regulated activation of CD4 T cells and Th1 cell differentiation, eventually leading to the exacerbation of LN.

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Section: Discussionsupporting

confidence: 86%

Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis

Masuda

Maeda

Sato

et al. 2017

The American Journal of Pathology

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“…It has been established that immune signalling contributes significantly to changes in the rewarding pathways of the brain induced by drugs of abuse [28], suggesting that endogenous modulators of immune response could be considered as novel pharmacological targets in addictive disorders. Very interestingly, MK is a known regulator of innate immune response [29]. MK is known to modulate expression of proinflammatory cytokines and the expansion of regulatory T-cells [30].…”

Section: Discussionmentioning

confidence: 99%

Genetic inactivation of midkine modulates behavioural responses to ethanol possibly by enhancing GABA(A) receptor sensitivity to GABA(A) acting drugs

Vicente-Rodríguez

Pérez-Garcı́a

Haro

et al. 2014

Behavioural Brain Research

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Midkine (MK) is a cytokine with important functions in dopaminergic neurons that is found upregulated in the prefrontal cortex of alcoholics. We have studied the behavioural effects of ethanol in MK genetically deficient (MK-/-) and wild type (MK+/+) mice. A low dose of ethanol (1.0g/kg), unable to cause conditioned place preference (CPP) in MK+/+ mice, induced a significant CPP in MK-/- mice, suggesting that MK prevents the rewarding effects of low doses of ethanol. However, this difference between genotypes is lost when a higher, rewarding, dose of ethanol (2.0g/kg) is used. Accordingly, the anxiolytic effects of 1.0mg/kg diazepam, other GABA(A) acting drug, were significantly enhanced in MK-/- mice compared to MK+/+ mice; however, 2.0mg/kg diazepam caused increased anxiolytic effects in MK+/+ mice. In addition, MK-/- mice showed a significant delayed recovery from ethanol (2.0g/kg)-induced ataxia whereas the sedative effects induced by ethanol (3.6g/kg), tested in a loss of righting reflex paradigm, were found to be similar in MK-/- and MK+/+ mice. The data indicate that MK differentially regulates the behavioural responses to ethanol. The results suggest that differences in the sensitivity of GABA(A) receptors to GABA(A) acting drugs caused by genetic inactivation of MK could underlie the different behavioural responses to ethanol in MK-/- mice. Overall, these results suggest that MK may be a novel genetic factor of importance in alcohol use disorders, and that potentiation of MK signalling pathway may be a promising therapeutic strategy in the treatment of these disorders.

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“…We also previously observed that FSTL3 is elevated, compared to healthy controls, in the sera, PBMCs, and skin of patients with dcSSc [ 28 ]. The growth factor, MDK, has been implicated in the pathogenesis of hypertension, kidney disease, and lung fibrosis [ 29 – 31 ].…”

Section: Discussionmentioning

confidence: 99%

Serum biomarker for diagnostic evaluation of pulmonary arterial hypertension in systemic sclerosis

et al. 2018

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BackgroundSystemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is one of the leading causes of death in SSc. Identification of a serum-based proteomic diagnostic biomarker for SSc-PAH would allow for rapid non-invasive screening and could positively impact patient survival. Identification and validation of novel proteins could potentially facilitate the identification of SSc-PAH, and might also point to important protein mediators in pathogenesis.MethodsThirteen treatment-naïve SSc-PAH patients had serum collected at time of diagnosis and were used as the discovery cohort for the protein-expression biomarker. Two proteins, Midkine and Follistatin-like 3 (FSTL3) were then validated by enzyme-linked immunosorbent assays. Midkine and FSTL3 were tested in combination to identify SSc-PAH and were validated in two independent cohorts of SSc-PAH (n = 23, n = 11).ResultsEighty-two proteins were found to be differentially regulated in SSc-PAH sera. Two proteins (Midkine and FSTL3) were also shown to be elevated in publicly available data and their expression was evaluated in independent cohorts. In the validation cohorts, the combination of Midkine and FSTL3 had an area under the receiver operating characteristic curve (AUC) of 0.85 and 0.92 with respective corresponding measures of sensitivity of 76% and 91%, and specificity measures of 76% and 80%.ConclusionsThese findings indicate that there is a clear delineation between overall protein expression in sera from SSc patients and those with SSc-PAH. The combination of Midkine and FSTL3 can serve as an SSc-PAH biomarker and are potential drug targets for this rare disease population.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1679-8) contains supplementary material, which is available to authorized users.

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Midkine as a regulator of B cell survival in health and disease

Cited by 13 publications

References 89 publications

Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis

Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis

Genetic inactivation of midkine modulates behavioural responses to ethanol possibly by enhancing GABA(A) receptor sensitivity to GABA(A) acting drugs

Serum biomarker for diagnostic evaluation of pulmonary arterial hypertension in systemic sclerosis

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