Transmembrane TNF-alpha reverse signaling leading to TGF-beta production is selectively activated by TNF targeting molecules: Therapeutic implications

Szondy, Zsuzsa; Pallai, Anna

doi:10.1016/j.phrs.2016.11.025

Cited by 71 publications

(55 citation statements)

References 105 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These receptors mediate nuclear signaling via Smad phosphorylation, suggesting that Smad or TGF-β signaling pathways mediate BMP9-induced osteogenesis in GC-1spg cells. Related pathways, including TNF [84,85], MAPK [86,87], Wnt [68], and Notch signaling pathways [14,27,53], may also play a role. In our study, KEGG pathway analysis of differentially expressed lncRNA, mRNA, circRNA, and miRNA shows that BMP9 treatment is involved in the cell cycle, focal adhesion, chemokine signaling, and the ErbB signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells

Zhang

Xu²,

Chen³

et al. 2019

Preprint

View full text Add to dashboard Cite

30Germ cell 1 spermatogonial (GC-1spg) cells are multipotent progenitor cells. We 31 previously confirmed that bone morphogenetic protein (BMP) 9 is among the most 32 osteogenic BMPs. However, whether GC-1spg cells are driven toward osteogenic 33 differentiation under proper stimuli is uncertain. Additionally, the molecular 34 mechanism of BMP9 remains unclear. In the present study, we aimed to determine 35 whether BMP9 can induce osteogenic differentiation of GC-1spg cells. Recombinant 36 adenoviruses were generated by the AdEasy system to regulate the BMP9 expression in 37 GC-1spg cells. We identified osteogenic markers by real-time PCR and staining 38 techniques in vitro. Ectopic ossification assays and histological analysis were also 39 performed to verify the in vivo activity of BMP9. Finally, potential signaling pathways 40 of BMP9 were assessed by transcriptome sequencing and KEGG enrichment analysis. 41Using recombinant adenoviruses, we demonstrate that BMP9 upregulates osteogenic 42 markers including Runx2, osteocalcin, osteopontin, and Sox9. BMP9 also activates 43 alkaline phosphatase activity and calcium deposition in GC-1spg cells. In vivo results 44show that BMP9 overexpression in GC-1spg cells promotes ectopic bone formation and 45 chondrogenesis. In addition, RNA-sequencing and KEGG pathway analysis 3 46 demonstrate that several signaling pathways are involved in BMP9-mediated 47 osteogenesis. GC-1spg cells not only maintain spermatogenesis but also retain the 48 ability to form bone tissue. Therefore, BMP9 activity in GC-1spg cells may help 49 identify signaling pathways implicated in bone formation and could be of use in 50 regenerative medicine. 51 Keywords: Bone morphogenetic protein 9, RNA-seq, KEGG pathway analysis, 52 recombinant adenovirus, chondrogenesis 53 Introduction 54 Germ cell 1 spermatogonial (GC-1spg) cells are mouse spermatogonia that are 55 immortalized by the SV40 large T antigen [1]. These cells can differentiate into diverse cell 56 types or undergo self-renewal, depending on different factors [2,3,4]. GC-1spg cells are 57 largely involved in spermatogenesis and have mesenchymal stem cell (MSC) differentiation 58 potential [5,6,7,8]. In other words, GC-1spg cells can differentiate into different cell types, 59including those of the osteogenic, chondrogenic, or adipogenic lineages [9,10,11,12]. 60However, several molecular events [13,14] and factors are involved in osteogenic 61 differentiation of MSCs. Importantly, bone morphogenetic proteins (BMPs) are essential for 62 this process [15,16,17]. 63 BMPs, members of the TGF-β superfamily, are required for bone formation, stem cell 64 differentiation, and male reproduction [15,16,18,19,20]. Thus far, more than 15 different 65 BMPs have been identified. Our previous work showed that BMP9 is the most osteogenic 66 BMP [21,22,23,24]. BMP9, also known as growth differentiation factor 2 (GDF-2)[25], was 67 originally isolated from the fetal mouse liver [25,26]. Bone formation involves BMP9 acting 68 through the Notch signaling ...

show abstract

Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells

Zhang

Xu²,

Chen³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Binding of IL‐17A with its receptor activates the transcription of nuclear factor‐κB leading to pro‐inflammatory cytokine production such as IL‐6, TNF‐α and IL‐1 . IL‐17 acts with IFN‐γ by increasing the production and release of IL‐6, IL‐8 and other cytokines by keratinocytes . In addition, IFN‐γ stimulates the expression of intercellular adhesion molecules‐1 (ICAM‐1) by keratinocytes, thus allowing the interaction between lymphocytes and endothelial cells, as well as the expression of chemokines as CXCL9, CXCL10, CXCL11 and their receptors such as CXCR3 .…”

Section: Introductionmentioning

confidence: 99%

“…IL‐17 and IL‐22 mediate different pathways associated with clinical aspects of psoriasis: IL‐17 is more pro‐inflammatory, while IL‐22 retards keratinocyte differentiation . On the other hand, the expression of Th2 cytokines IL‐4 and‐13 is reduced in psoriatic lesions and is proved to inhibit keratinocyte activation through STAT6, SOCS1 and SOCS3 . Even Treg subset is dysregulated in psoriasis, getting the basis for chronicity …”

Section: Introductionmentioning

confidence: 99%

Interleukin‐17A affects extracellular vesicles release and cargo in human keratinocytes

Mangino

Iuliano

Carlomagno

et al. 2019

Experimental Dermatology

View full text Add to dashboard Cite

Psoriasis is a chronic inflammatory systemic disease caused by deregulation of the interleukin‐23/‐17 axis that allows the activation of Th17 lymphocytes and the reprogramming of keratinocytes proliferative response, thereby inducing the secretion of cyto‐/chemokines and antimicrobial peptides. Beside cell‐to‐cell contacts and release of cytokines, hormones and second messengers, cells communicate each other through the release of extracellular vesicles containing DNA, RNA, microRNAs and proteins. It has been reported the alteration of extracellular vesicles trafficking in several diseases, but there is scarce evidence of the involvement of extracellular vesicles trafficking in the pathogenesis of psoriasis. The main goal of the study was to characterize the release, the cargo content and the capacity to transfer bioactive molecules of extracellular vesicles produced by keratinocytes following recombinant IL‐17A treatment if compared to untreated keratinocytes. A combined approach of standard ultracentrifugation, RNA isolation and real‐time RT‐PCR techniques was used to characterize extracellular vesicles cargo. Flow cytometry was used to quantitatively and qualitatively analyse extracellular vesicles and to evaluate cell‐to‐cell extracellular vesicles transfer. We report that the treatment of human keratinocytes with IL‐17A significantly modifies the extracellular vesicles cargo and release. Vesicles from IL‐17A‐treated cells display a specific pattern of mRNA which is undid by IL‐17A neutralization. Extracellular vesicles are taken up by acceptor cells irrespective of their content but only those derived from IL‐17A‐treated cells enable recipient cells to express psoriasis‐associated mRNA. The results imply a role of extracellular vesicles in amplifying the pro‐inflammatory cascade induced in keratinocyte by pro‐psoriatic cytokines.

show abstract

“…Many cells, including T cells, express mTNFa in addition to soluble TNFa. It has been demonstrated that mTNFa, once engaged by TNFa receptor or anti-TNFa, is capable of transmitting signals back into mTNFa-bearing cells [30]. Thus, it is possible that etanercept and adalimumab counteract the effect of anti-CD28 through reverse signaling.…”

Section: Discussionmentioning

confidence: 99%

Utilizing a PTPN22 gene signature to predict response to targeted therapies in rheumatoid arthritis

Chang

Tomita

et al. 2019

Preprint

View full text Add to dashboard Cite

A patent application based on the results described in this manuscript has been submitted.YCL is an unpaid advisory board member of Eli Lilly and receives a grant from Pfizer.There is no other conflict of interest. AbstractDespite the development of several targeted therapies for rheumatoid arthritis (RA), there is still no reliable drug-specific predictor to assist rheumatologists in selecting the most effective targeted therapy for each patient. Recently, a gene signature caused by impaired induction of PTPN22 in anti-CD3 stimulated peripheral blood mononuclear cells (PBMC) was observed in healthy at-risk individuals. However, the downstream target genes of PTPN22 and the molecular mechanisms regulating its expression are still poorly understood. Here we report that the PTPN22 gene signature is also present in PBMC from patients with active RA and can be reversed after effective treatment. The expression of PTPN22 correlates with that of more than 1000 genes in Th cells of anti-CD3 stimulated PBMC of healthy donors and is inhibited by TNFa or CD28 signals, but not IL-6, through distinct mechanisms. In addition, the impaired induction of PTPN22 in PBMC of patients with active RA can be normalized in vitro by several targeted therapies. More importantly, the in vitro normalization of PTPN22 expression correlates with clinical response to the targeted therapies in a longitudinal RA cohort. Thus, in vitro normalization of PTPN22 expression by targeted therapies can potentially be used to predict clinical response in a drug-specific manner.

show abstract

Transmembrane TNF-alpha reverse signaling leading to TGF-beta production is selectively activated by TNF targeting molecules: Therapeutic implications

Cited by 71 publications

References 105 publications

Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells

Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells

Interleukin‐17A affects extracellular vesicles release and cargo in human keratinocytes

Utilizing a PTPN22 gene signature to predict response to targeted therapies in rheumatoid arthritis

Contact Info

Product

Resources

About