TNFα and IL-1β influence the differentiation and migration of murine MSCs independently of the NF-κB pathway

Abstract

IntroductionMesenchymal stem cells (MSCs) have the ability to repair and regenerate tissue, home to sites of inflammation, and evade the host immune system. As such, they represent an attractive therapy for the treatment of autoimmune inflammatory diseases. However, results from in vivo murine studies in inflammatory arthritis have been conflicting, and this may be due to the genetic background of the MSCs used. It is known that the inflammatory milieu may influence properties of MSCs and that, in the case of human bone marrow-derived MSCs, this may be mediated by the nuclear factor-kappa-B (NF-κB) pathway. We sought to determine whether pro-inflammatory cytokines altered the differentiation and migration capacity of murine MSCs from different mouse strains and whether this was mediated by NF-κB.MethodsThe differentiation and migration of FVB and BALB/c MSCs were carried out in the presence of varying concentrations of tumor necrosis factor-alpha (TNFα) and interleukin (IL)-1β, and the NF-κB pathway was inhibited in one of two ways: either by transduction of MSCs with an adenoviral vector expressing a super-repressor of NF-κB or by the addition of curcumin to culture media.ResultsBoth BALB/c and FVB MSCs were sensitive to the effect of pro-inflammatory cytokines in vitro. TNFα and IL-1β suppressed BALB/c osteogenesis and adipogenesis and FVB osteogenesis. The migration of both cell types toward media containing fetal bovine serum was augmented by pre-stimulation with either cytokine. In neither cell type were the cytokine effects reversed by abrogation of the NF-κB pathway.ConclusionsThese data show that murine MSCs from different genetic backgrounds may be influenced by an inflammatory milieu in a manner that is not mediated by NF-κB, as is the case for human MSCs. This is not mediated by NF-κB. These findings are important and should influence how in vivo trials of murine MSCs are interpreted and the future development of pre-clinical studies in inflammatory diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/scrt492) contains supplementary material, which is available to authorized users.

The effect of pro-inflammatory cytokines on immunophenotype, differentiation capacity and immunomodulatory functions of human mesenchymal stem cells

“…On the other hand, Lacey et al have shown that osteogenic differentiation from the MSCs population is suppressed by pro-inflammatory cytokines (IL-1 and TNF-a) [42]. Sullivan et al demonstrated the same results as well as suppression of adipogenic differentiation by proinflammatory cytokines [43]. Related to effect of IL-6 on MSCs behavior, Pricola et al have shown that IL-6 inhibits adipogenic and chondrogenic differentiation of MSCs and maintains MSCs in undifferentiated state [44].…”

Concentration‐dependent, dual roles of IL‐10 in the osteogenesis of human BMSCsviaP38/MAPK and NF‐κB signaling pathways

“…The fracture hematoma is a rich medium abundant in inflammatory molecules, including IL-1b, IL-6, IL-8, IL-10, HMGB1, and TNF-a, which regulate the inflammatory response and initiate chemotaxis and cell proliferation and differentiation (8,(35)(36)(37). Many reports have investigated the relationship between osteogenic differentiation and IL-1b, IL-6, IL-8, and TNF-a (24,(38)(39)(40)(41). We also investigated the mechanisms of the osteogenesis of HMGB1 on MSCs (42,43).…”

Melatonin reversed tumor necrosis factor‐alpha‐inhibited osteogenesis of human mesenchymal stem cells by stabilizing SMAD1 protein

“…Tumor necrosis factor‐alpha has been documented to regulate bone remodeling by suppressing osteogenesis and activating osteoclastogenesis . Quite a few signaling pathways are involved in mediating the effects of TNFα on osteogenesis as reported . Among them, SMURF1 seems particularly notable because SMURF1 itself is a well‐known negative regulator of bone formation.…”

“…2,3 Quite a few signaling pathways are involved in mediating the effects of TNFα on osteogenesis as reported. 6,8,9,[26][27][28]33,34 Among them, SMURF1 seems particularly notable because SMURF1 itself is a well-known negative regulator of bone formation. Osteoblast-specific Smurf1 transgenic mice showed significantly less bone formation.…”