Caspase-8 regulates the expression of pro- and anti-inflammatory cytokines in human bone marrow-derived mesenchymal stromal cells.
BACKGROUND
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 TGFβ whereas LPS reduced HGF expression only. Notably, caspase-8 was involved in the induction of IL- IL-1β, IL-6, CXCL10, and in the inhibition of HGF and TGFβ.


CONCLUSIONS
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.
The KG Jebsen Center for Myeloma Research and Faculty of Medicine, Department of Cancer Research and Molecular Medicine Norwegian University of Science and Technology (NTNU) Trondheim Norway.
Siv H
SH
Moen
The KG Jebsen Center for Myeloma Research and Faculty of Medicine, Department of Cancer Research and Molecular Medicine Norwegian University of Science and Technology (NTNU) Trondheim Norway.
Marita
M
Westhrin
Centre of Molecular Inflammation Rearch (CEMIR) NTNU Trondheim Norway.
Muhammad
M
Zahoor
The KG Jebsen Center for Myeloma Research and Faculty of Medicine, Department of Cancer Research and Molecular Medicine Norwegian University of Science and Technology (NTNU) Trondheim Norway.
Nikolai N
NN
Nørgaard
The KG Jebsen Center for Myeloma Research and Faculty of Medicine, Department of Cancer Research and Molecular Medicine Norwegian University of Science and Technology (NTNU) Trondheim Norway.
Hanne
H
Hella
The KG Jebsen Center for Myeloma Research and Faculty of Medicine, Department of Cancer Research and Molecular Medicine Norwegian University of Science and Technology (NTNU) Trondheim Norway.
Berit
B
Størdal
The KG Jebsen Center for Myeloma Research and Faculty of Medicine, Department of Cancer Research and Molecular MedicineNorwegian University of Science and Technology (NTNU)TrondheimNorway; Centre of Molecular Inflammation Rearch (CEMIR)NTNUTrondheimNorway.
Anders
A
Sundan
The KG Jebsen Center for Myeloma Research and Faculty of Medicine, Department of Cancer Research and Molecular MedicineNorwegian University of Science and Technology (NTNU)TrondheimNorway; Centre of Molecular Inflammation Rearch (CEMIR)NTNUTrondheimNorway.
Nadra J
NJ
Nilsen
The KG Jebsen Center for Myeloma Research and Faculty of Medicine, Department of Cancer Research and Molecular Medicine Norwegian University of Science and Technology (NTNU) Trondheim Norway.
Anne-Marit
AM
Sponaas
The KG Jebsen Center for Myeloma Research and Faculty of Medicine, Department of Cancer Research and Molecular MedicineNorwegian University of Science and Technology (NTNU)TrondheimNorway; Centre of Molecular Inflammation Rearch (CEMIR)NTNUTrondheimNorway.
Therese
T
Standal
Caspase‐8; cytokines; human bone marrow‐derived MSCs (hBMSCs)