Interferon-γ and Tumor Necrosis Factor-α Differentially Affect Cytokine Expression and Migration Properties of Mesenchymal Stem Cells

Abstract

Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the capacity to differentiate into different tissue cell types such as chondrocytes, osteocytes, and adipocytes. In addition, they can home to damaged, in-flamed, and malignant tissues and display immunomodulatory properties. Since tissue-derived factors might modulate these properties, we decided to explore the impact of prototypic tissue-derived inflammatory cytokines such as TNF-α and IFN-γ on immunomodulatory MSCs functions. To this end, we used primary bone marrow and cord blood-derived MSCs as well as an immortalized MSC line (V54/2) as model systems. We demonstrate that under unstimulated conditions, V54/2 cells constitutively express low levels of indoleamine 2,3-dioxygenase (IDO), exert an immunosuppressive effect on activated T-lymphocyte proliferation, secrete a distinct set of cytokines, and express a wide range of chemokine receptors. Upon stimulation, the proinflammatory cytokines IFN-γ and TNF-α did not inhibit suppression of T-cell proliferation, although IDO expression was up-regulated by IFN-γ. In contrast, TNF-α but not IFN-γ amplified the cytokine production of V54/2 and primary MSCs. Interestingly, IFN-γ was superior to TNF-α in up-regulating expression of chemokine receptors and migration of the V54/2 cell line, while TNF-α was the predominant regulator of migration in primary MSCs. Altogether, our data show that properties of MSCs depend on local environmental factors. In particular, we have shown that IFN-γ and TNF-α differentially regulate cytokine expression and migration of MSCs.