Dataset Information

Caspase-8 regulates the expression of pro- and anti-inflammatory cytokines in human bone marrow-derived mesenchymal stromal cells.

ABSTRACT:

Introduction

Mesenchymal stem cells, also called mesenchymal stromal cells, MSCs, have great potential in stem cell therapy partly due to their immunosuppressive properties. How these cells respond to chronic inflammatory stimuli is therefore of importance. Toll-like receptors (TLR)s are innate immune receptors that mediate inflammatory signals in response to infection, stress, and damage. Caspase-8 is involved in activation of NF-kB downstream of TLRs in immune cells. Here we investigated the role of caspase-8 in regulating TLR-induced cytokine production from human bone marrow-derived mesenchymal stromal cells (hBMSCs).

Methods

Cytokine expression in hBMCs in response to poly(I:C) and LPS was evaluated by PCR, multiplex cytokine assay, and ELISA. TLR3, TRIF, and caspase-8 were silenced using siRNA. Caspase-8 was also inhibited using a caspase-8 inhibitor, z-IEDT.

Results

We found that TLR3 agonist poly(I:C) and TLR4 agonist LPS induced secretion of several pro-inflammatory cytokines in a TLR-dependent manner which required the TLR signaling adaptor molecule TRIF. Further, poly(I:C) reduced the expression of anti-inflammatory cytokines HGF and TGF? whereas LPS reduced HGF expression only. Notably, caspase-8 was involved in the induction of IL- IL-1?, IL-6, CXCL10, and in the inhibition of HGF and TGF?.

Conclusion

Caspase-8 appears to modulate hBMSCs into gaining a pro-inflammatory phenotype. Therefore, inhibiting caspase-8 in hBMSCs might promote an immunosuppressive phenotype which could be useful in clinical applications to treat inflammatory disorders.

SUBMITTER: Moen SH

PROVIDER: S-EPMC5004287 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Publications

Caspase-8 regulates the expression of pro- and anti-inflammatory cytokines in human bone marrow-derived mesenchymal stromal cells.

Moen Siv H SH Westhrin Marita M Zahoor Muhammad M Nørgaard Nikolai N NN Hella Hanne H Størdal Berit B Sundan Anders A Nilsen Nadra J NJ Sponaas Anne-Marit AM Standal Therese T

Immunity, inflammation and disease 20160721 3

<h4>Introduction</h4>Mesenchymal stem cells, also called mesenchymal stromal cells, MSCs, have great potential in stem cell therapy partly due to their immunosuppressive properties. How these cells respond to chronic inflammatory stimuli is therefore of importance. Toll-like receptors (TLR)s are innate immune receptors that mediate inflammatory signals in response to infection, stress, and damage. Caspase-8 is involved in activation of NF-kB downstream of TLRs in immune cells. Here we investigat ...[more]

PMID: 27621815

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Project description:BACKGROUND: Wharton's jelly derived stem cells (WJMSCs) are gaining attention as a possible clinical alternative to bone marrow derived mesenchymal stem cells (BMMSCs) owing to better accessibility, higher expansion potential and low immunogenicity. Usage of allogenic mesenchymal stem cells (MSC) could be permissible in vivo only if they retain their immune properties in an inflammatory setting. Thus the focus of this study is to understand and compare the immune properties of BMMSCs and WJMSCs primed with key pro-inflammatory cytokines, Interferon-gamma (IFNgamma) and Tumor Necrosis Factor-alpha (TNFalpha). METHODOLOGY/PRINCIPAL FINDINGS: Initially the effect of priming on MSC mediated suppression of alloantigen and mitogen induced lymphoproliferation was evaluated in vitro. Treatment with IFNgamma or TNFalpha, did not ablate the immune-suppression caused by both the MSCs. Extent of immune-suppression was more with WJMSCs than BMMSCs in both the cases. Surprisingly, priming BMMSCs enhanced suppression of mitogen driven lymphoproliferation only; whereas IFNgamma primed WJMSCs were better suppressors of MLRs. Further, kinetic analysis of cytokine profiles in co-cultures of primed/unprimed MSCs and Phytohematoagglutinin (PHA) activated lymphocytes was evaluated. Results indicated a decrease in levels of pro-inflammatory cytokines. Interestingly, a change in kinetics and thresholds of Interleukin-2 (IL-2) secretion was observed only with BMMSCs. Analysis of activation markers on PHA-stimulated lymphocytes indicated different expression patterns in co-cultures of primed/unprimed WJMSCs and BMMSCs. Strikingly, co-culture with WJMSCs resulted in an early activation of a negative co-stimulatory molecule, CTLA4, which was not evident with BMMSCs. A screen for immune suppressive factors in primed/unprimed WJMSCs and BMMSCs indicated inherent differences in IFNgamma inducible Indoleamine 2, 3-dioxygenase (IDO) activity, Hepatocyte growth factor (HGF) and Prostaglandin E-2 (PGE2) levels which could possibly influence the mechanism of immune-modulation. CONCLUSION/SIGNIFICANCE: This study demonstrates that inflammation affects the immune properties of MSCs distinctly. Importantly different tissue derived MSCs could utilize unique mechanisms of immune-modulation.

Project description:BackgroundMesenchymal stem/stromal cells (MSCs) and macrophages are critical components in many tissue microenvironments, including that in adipose tissue. The close interaction between MSCs and macrophages modulates various adipose-related disease development. However, the effects of macrophages on the fate of MSCs remain largely elusive. We here studied the effect of macrophages on the adipogenic differentiation of MSCs.MethodsMacrophages were obtained from THP-1 cells treated with phorbol-12-myristate-13-acetate (PMA). The induced matured macrophages were then induced to undergo classically activated macrophage (M1) or alternatively activated macrophage (M2) polarization with Iipopolysaccharide (LPS)/interferon (IFN)-γ and interleukin (IL)-4/IL-13, respectively. The supernatants derived from macrophages under different conditions were applied to cultured human adipose tissue-derived mesenchymal stem/stromal cells (hADSCs) undergoing adipogenic differentiation. Adipogenic differentiation was evaluated by examining Oil Red O staining of lipid droplets and the expression of adipogenesis-related genes with real-time quantitative polymerase chain reaction (Q-PCR) and western blot analysis.ResultsThe adipogenic differentiation of hADSCs was impaired when treated with macrophage-derived supernatants, especially that from the M1-polarized macrophage (M1-sup). The inhibitory effect was found to be mediated by the inflammatory cytokines, mainly tumor necrosis factor-α (TNF-α) and IL-1β. Blocking TNF-α and IL-1β with neutralizing antibodies partially alleviated the inhibitory effect of M1-sup.ConclusionMacrophage-derived supernatants inhibited the adipogenic differentiation of hADSCs in vitro, irrespective of the polarization status (M0, M1 or M2 macrophages). M1-sup was more potent because of the higher expression of pro-inflammatory cytokines. Our findings shed new light on the interaction between hADSCs and macrophages and have implications in our understanding of disrupted adipose tissue homeostasis under inflammation.

Dataset Information

Caspase-8 regulates the expression of pro- and anti-inflammatory cytokines in human bone marrow-derived mesenchymal stromal cells.

Introduction

Methods

Results

Conclusion

Publications

Caspase-8 regulates the expression of pro- and anti-inflammatory cytokines in human bone marrow-derived mesenchymal stromal cells.

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