Novel Mechanism of Inhibition of Dendritic Cells Maturation by Mesenchymal Stem Cells via Interleukin-10 and the JAK1/STAT3 Signaling Pathway

Abstract

Mesenchymal stem cells (MSCs) can suppress dendritic cells (DCs) maturation and function, mediated by soluble factors, such as indoleamine 2,3-dioxygenase (IDO), prostaglandin E2 (PGE2), and nitric oxide (NO). Interleukin-10 (IL-10) is a common immunosuppressive cytokine, and the downstream signaling of the JAK-STAT pathway has been shown to be involved with DCs differentiation and maturation in the context of cancer. Whether IL-10 and/or the JAK-STAT pathway play a role in the inhibitory effect of MSCs on DCs maturation remains controversial. In our study, we cultured MSCs and DCs derived from rat bone marrow under different culturing conditions. Using Transwell plates, we detected by ELISA that the level of IL-10 significantly increased in the supernatants of MSC-DC co-cultures at 48 hours. The cell immunofluorescence assay suggested that the MSCs secreted more IL-10 than the DCs in the co-cultures. Adding exogenous IL-10 to the DCs monoculture or MSC-DC co-cultures stimulated IL-10 and led to a decrease in IL-12, and lower expression of the DCs surface markers CD80, CD86, OX62, MHC-II and CD11b/c. Supplementing the culture with an IL-10 neutralizing antibody (IL-10NA) showed precisely the opposite effect of adding IL-10. Moreover, we demonstrated that the JAK-STAT signaling pathway is involved in inhibiting DCs maturation. Both JAK1 and STAT3 expression and IL-10 secretion decreased markedly after adding a JAK inhibitor (AG490) to the co-culture plate. We propose that there is an IL-10 positive feedback loop, which may explain our observations of elevated IL-10 and enhanced JAK1 and STAT3 expression. Overall, we demonstrated that MSCs inhibit the maturation of DCs through the stimulation of IL-10 secretion, and by activating the JAK1 and STAT3 signaling pathway.

Secretion of immunoregulatory cytokines by mesenchymal stem cells

“…As described above, MSCs can suppress dendritic cell maturation and function, mediated by soluble factors which also include IDO. It was demonstrated that MSCs inhibit the maturation of DCs through the stimulation of IL-10 secretion and by activating the JAK1 and STAT3 signaling pathway [186] .…”

In Vitro Evidence of the Presence of Mesenchymal Stromal Cells in Cervical Cancer and Their Role in Protecting Cancer Cells from Cytotoxic T Cell Activity

“…Such IL-10 levels may simply be the sum of the individual production of IL-10 by MSCs and tumor cells in cocultures with NCx-MSCs, but in those with BM-MSCs or CeCa-MSCs, where the IL-10 production was higher than the proper sum of the individual cell types, these differences could be the result of the cross talk between CaSki and MSCs during cell coculture through transwell plates, as recently was reported by Liu and cols. [45], who found that ratderived BM-MSCs increased the IL-10 intracellular expression after transwell cell coculture with dendritic cells, suggesting MSC activation in such cell cocultures. In this regard and in trying to determine which is the source of the IL-10 in our cocultures, we have observed, in preliminary assays, that BM-MSCs and CeCa-MSCs in coculture with CaSki cells increased the IL-10 intracellular expression in comparison with their respective monocultures, however, it is possible also that CaSki cells increase IL-10 expression; these two aspects are under investigation.…”

Role of Mesenchymal Multipotent Stromal Cells in Remodeling of Bone Defects

“…Введенные локально, МСК привлекают макрофаги и способствуют их по-ляризации в регуляторный фенотип [16]. Более того, фагоцитоз фрагментов погибших МСК ма-крофагами стимулирует их регенеративную и им-муномодулирующую функцию [38]. Влияние MСК на функцию макрофагов и остеокластов имеет важное значение для оценки целесообраз-ности использования этих клеток-предшествен-ников при создании биоимплантатов костей [18].…”

“…Современные стратегии создания ткане-инженерных конструкций активно используют МСК для улучшения интеграции имплантатов и предотвращения иммунологического отторже-ния. В доклинических исследованиях показано, что заселение биосовместимых материалов МСК значительно повышает остеокондуктивность и улучшает интеграцию имплантатов [30,38]. Первые клинические испытания скаффолдов, заселенных МСК, подтверждают их эффектив-ность [20].…”

“…МСК обладают мощными иммуномодулиру-ющими свойствами, как правило, негативно вли-яющими на пролиферацию и дифференцировку различных иммунных клеток [38]. Механизмы иммуномодуляции МСК еще до конца не выяс-…”