Concentration‐dependent, dual roles of IL‐10 in the osteogenesis of human BMSCs<i>via</i>P38/MAPK and NF‐κB signaling pathways

Chen, Erman; Liu, Guanyi; Zhou, Xiaopeng; Zhang, Wei; Wang, Cong; Hu, Dongcai; Xue, Deting; Pan, Zhijun

doi:10.1096/fj.201701256rrr

Cited by 57 publications

(56 citation statements)

References 59 publications

(70 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Phenotypic switching of macrophages during fracture repair leads to the production of IL-10, found in serum samples from fracture hematomas of patients at concentrations around 1 ng/ml [36]. A recent study showed that recombinant IL-10 can enhance MSC osteogenesis via the p38/mitogen-activated protein kinase (MAPK) signaling pathway [25]. To our knowledge, our study is the first to demonstrate that IL-10 secreted by macrophages regulates MSC osteogenic differentiation.…”

Section: Discussionmentioning

confidence: 59%

See 1 more Smart Citation

Influence of inflammatory conditions provided by macrophages on osteogenic ability of mesenchymal stem cells

et al. 2020

View full text Add to dashboard Cite

Background: The mechanisms by which macrophage phenotype contributes to mesenchymal stem cells (MSC)mediated bone repair remain unclear. In this work, we investigated the influence of factors released by human macrophages polarized to a pro-inflammatory or an anti-inflammatory phenotype on the ability of human MSC to attach, migrate, and differentiate toward the osteoblastic lineage. We focused on the role of TNF-α and IL-10, key pro-inflammatory and anti-inflammatory cytokines, respectively, in regulating MSC functions. Methods: MSC were treated with media conditioned by pro-inflammatory or anti-inflammatory macrophages to study their influence in cell attachment, migration, and osteogenic differentiation. The involvement of TNF-α and IL-10 in the regulation of MSC functions was investigated using neutralizing antibodies and recombinant cytokines. Results: Treatment of MSC with media conditioned by pro-inflammatory or anti-inflammatory macrophages promoted cell elongation and enhanced MSC ability to attach and migrate. These effects were more noticeable when MSC were treated with media from pro-inflammatory macrophages. Interestingly, MSC osteogenic activity was enhanced by factors released by anti-inflammatory macrophages, but not by pro-inflammatory macrophages. Significant IL-10 levels originated from anti-inflammatory macrophages enhanced MSC osteogenesis by increasing ALP activity and mineralization in MSC layers cultured under osteogenic conditions. Moreover, macrophage-derived IL-10 regulated the expression of the osteogenic markers RUNX2, COL1A1, and ALPL. Notably, low TNF-α levels secreted by anti-inflammatory macrophages increased ALP activity in differentiating MSC whereas high TNF-α levels produced by pro-inflammatory macrophages had no effects on osteogenesis. Experiments in which MSC were treated with cytokines revealed that IL-10 was more effective in promoting matrix maturation and mineralization than TNF-α. Conclusions: Factors secreted by pro-inflammatory macrophages substantially increased MSC attachment and migration whereas those released by anti-inflammatory macrophages enhanced MSC osteogenic activity as well as cell migration. IL-10 was identified as an important cytokine secreted by anti-inflammatory macrophages that potentiates MSC osteogenesis. Our findings provide novel insights into how environments provided by macrophages regulate MSC osteogenesis, which may be helpful to develop strategies to enhance bone regeneration.

show abstract

Section: Discussionmentioning

confidence: 59%

“…We recently reported that IL-10 originated from pro-resolving macrophages enhances MSC immunomodulatory potential in vitro [18]. In addition, a recent study showed that physiological doses of recombinant IL-10 stimulate MSC osteogenic differentiation while higher pathological doses inhibit it [25].…”

Section: Introductionmentioning

confidence: 99%

Influence of inflammatory conditions provided by macrophages on osteogenic ability of mesenchymal stem cells

et al. 2020

View full text Add to dashboard Cite

show abstract

“…As a key anti-inflammatory cytokine, IL-10 participates in immune response and regulates by multiple signaling pathways in the activated macrophages [29][30][31]. Previous studies have shown that PCV2 infection activates the PI3K/Akt pathway to suppress premature apoptosis for improved virus growth and aggravate the effects on autophagy and PCV2 replication [32,33].…”

Section: Discussionmentioning

confidence: 99%

Porcine Circovirus Type 2 Rep Enhances IL-10 Production in Macrophages via Activation of p38-MAPK Pathway

Wang

Shi

et al. 2019

Viruses

View full text Add to dashboard Cite

Porcine circovirus type 2 (PCV2) is one of the major threats to pig farms worldwide. Although PCV2 has been identified to promote IL-10 production, the detailed regulatory roles of PCV2 Rep for IL-10 production remain unclear. Herein, we first found that PCV2 Rep, rather than PCV1 Rep, enhanced IL-10 expression at the later phase of PCV2 infection in porcine alveolar macrophages (PAMs). Furthermore, we found that PCV2 Rep directly activated the p38-MAPK pathway to promote transcription factors NF-κB p50 and Sp1 binding to the il10 promoter, but PCV1 Rep did not. During PCV2 infection, however, PCV2 Rep promoted the binding activities of NF-κB p50 and Sp1 with the il10 promoter only at the later phase of PCV2 infection, since Rep proteins only expressed at the later phase of the infection. Moreover, silence of the thymine DNA glycosylase (TDG), a Rep-binding protein, significantly reduced the binding activities of NF-κB p50 and Sp1 with il10 promoter, resulting in the reduction of IL-10 production in PCV2-inoculated PAMs at the later phase of infection. Taken together, our results demonstrate that Rep proteins enhance IL-10 production during PCV2 infection of PAMs via activation of p38-MAPK pathways, in which host TDG is a critical mediator.

show abstract

“…AGN194310 might regulate chondrocyte proliferation and differentiation to maintain endochondral ossification through accession of NF-κB and reduction of p38 MAPK signaling pathway [34]. However, the mechanisms of crosstalk between p38 MAPK and NF-kB signaling are not fully clarified [35], and require further investigation of AGN194310 effects on NF-kB signaling in future studies.…”

Section: Discussionmentioning

confidence: 99%

Expression and Role of IL-1β Signaling in Chondrocytes Associated with Retinoid Signaling during Fracture Healing

Shimo

Takebe

Okui

et al. 2020

IJMS

View full text Add to dashboard Cite

The process of fracture healing consists of an inflammatory reaction and cartilage and bone tissue reconstruction. The inflammatory cytokine interleukin-1β (IL-1β) signal is an important major factor in fracture healing, whereas its relevance to retinoid receptor (an RAR inverse agonist, which promotes endochondral bone formation) remains unclear. Herein, we investigated the expressions of IL-1β and retinoic acid receptor gamma (RARγ) in a rat fracture model and the effects of IL-1β in the presence of one of several RAR inverse agonists on chondrocytes. An immunohistochemical analysis revealed that IL-1β and RARγ were expressed in chondrocytes at the fracture site in the rat ribs on day 7 post-fracture. In chondrogenic ATDC5 cells, IL-1β decreases the levels of aggrecan and type II collagen but significantly increased the metalloproteinase-13 (Mmp13) mRNA by real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. An RAR inverse agonist (AGN194310) inhibited IL-1β-stimulated Mmp13 and Ccn2 mRNA in a dose-dependent manner. Phosphorylated extracellular signal regulated-kinases (pERK1/2) and p-p38 mitogen-activated protein kinase (MAPK) were increased time-dependently by IL-1β treatment, and the IL-1β-induced p-p38 MAPK was inhibited by AGN194310. Experimental p38 inhibition led to a drop in the IL-1β-stimulated expressions of Mmp13 and Ccn2 mRNA. MMP13, CCN2, and p-p38 MAPK were expressed in hypertrophic chondrocytes near the invaded vascular endothelial cells. As a whole, these results point to role of the IL-1β via p38 MAPK as important signaling in the regulation of the endochondral bone formation in fracture healing, and to the actions of RAR inverse agonists as potentially relevant modulators of this process.

show abstract

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

Cited by 57 publications

References 59 publications

Influence of inflammatory conditions provided by macrophages on osteogenic ability of mesenchymal stem cells

Influence of inflammatory conditions provided by macrophages on osteogenic ability of mesenchymal stem cells

Porcine Circovirus Type 2 Rep Enhances IL-10 Production in Macrophages via Activation of p38-MAPK Pathway

Expression and Role of IL-1β Signaling in Chondrocytes Associated with Retinoid Signaling during Fracture Healing

Contact Info

Product

Resources

About