26
Stem Cells Dev. 2012 Jul 20;21(11):1948-55.
Diferential signalling through ALK-1 and ALK-5
regulates leptin expression in mesenchymal stem
cells.
Zeddou M, Relic B, Malaise O, Charlier E, Desoroux A, Beguin Y, de Seny D, Malaise MG.
Abstract
Leptin plays a central role in maintaining energy balance, with multiple other systemic
efects. Despite leptin importance in peripheral regulation of mesenchymal stem cells (MSC)
diferentiation, little is known about its expression mechanism. Leptin is often described as
adipokine, while it is expressed by other cell types. We have recently shown an in vitro
leptin expression, enhanced by glucocorticoids in synovial fbroblasts (SVF). Here, we inves-
tigated leptin expression in MSC from bone marrow (BM-MSC) and umbilical cord matrix
(UMSC). Results showed that BM-MSC, but not UMSC, expressed leptin that was strongly
enhanced by glucocorticoids. Transforming growth factor β1 (TGF-β1) markedly inhibited the
endogenous- and glucocorticoid-induced leptin expression in BM-MSC. Since TGF-β1 was
shown to signal via ALK-5-Smad2/3 and/or ALK-1-Smad1/5 pathways, we analyzed the
expression of proteins from both pathways. In BM-MSC, TGF-β1 increased phosphorylated
Smad2 (p-Smad2) expression, while ALK-5 inhibitor (SB431542) induced leptin expression
and signifcantly restored TGF-β1-induced leptin inhibition. In addition, both prednisolone
and SB431542 increased p-Smad1/5 expression. These results suggested the ALK-5-Smad2
pathway as an inhibitor of leptin expression, while ALK-1-Smad1/5 as an activator. Indeed,
Smad1 expression silencing induced leptin expression inhibition. Furthermore, prednisolone
enhanced the expression of TGF-βRII while decreasing p-Smad2 in BM-MSC and SVF but not
in UMSC. In vitro diferentiation revealed diferential osteogenic potential in SVF, BM-MSC,
and UMSC that was correlated to their leptin expression potential. Our results suggest that
ALK-1/ALK-5 balance regulates leptin expression in MSC. It also underlines UMSC as leptin
nonproducer MSC for cell therapy protocols where leptin expression is not suitable.
Int Arch Allergy Immunol. 2012;158(1):1-8.
Disturbedcytokineproductionatthesystemiclevelin
difcult-to-controlatopicasthma:evidenceforraised
interleukin-4 and decreased interferon-γ release
following lipopolysaccharide stimulation.
Manise M, Schleich F, Quaedvlieg V, Moermans C, Henket M, Sele J, Corhay JL, Louis R.
Abstract
BACKGROUND:
Disturbed cytokine production is thought to govern infammation in asthma, which, in its turn,
may lead to uncontrolled disease. The aim of this study was to assess the relationship between
cytokine production from blood leucocytes and the level of asthma control.
METHODS:
We compared the production of interleukin (IL)-4, IL-6, IL-10, interferon (IFN)-γ and tumour
necrosis factor-α from peripheral blood leucocytes in non-atopic healthy subjects (n = 22),
atopic non-asthmatics (n = 10), well-controlled asthmatics [Juniper asthma control question-
naire (ACQ) score <1.5; n = 20] and patients with uncontrolled asthma despite inhaled or
oral corticoids (ACQ score ≥1.5; n = 20). Fifty microlitres of peripheral blood was incubated
for 24 h with RPMIc, lipopolysaccharide (LPS; 1 ng/ml) or phytohaemagglutinin (1 μg/ml), and
cytokines were measured by immunotrapping (ELISA).
RESULTS:
Both controlled and uncontrolled asthmatics as well as atopic non-asthmatics spontaneously
produced more IL-4 than non-atopic healthy subjects (p < 0.001). IL-4 production induced by
LPS was signifcantly greater (p < 0.05) in both asthma groups compared to atopic non-asth-
matics and non-atopic healthy subjects. By contrast, IFN-γ release induced by LPS was lower
in uncontrolled asthmatics than in non-atopic healthy subjects (p < 0.05) and controlled asth-
matics (p < 0.05). IL-10 release after LPS was greater in uncontrolled asthmatics than in atopic
non-asthmatics (p < 0.05). No diference was observed regarding other cytokines.
CONCLUSION:
Blood cells from patients with difcult-to-control atopic asthma display highly skewed Th2
cytokine release following LPS stimulation.