Expression and function of Smad7 in autoimmune and inflammatory diseases

Hu, Yiping; He, Juan; He, Lianhua; Xu, Bihua; Wang, Qingwen

doi:10.1007/s00109-021-02083-1

Cited by 22 publications

(12 citation statements)

References 110 publications

(118 reference statements)

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“…In turn, P 4 inhibits TGFβ production [ 90 ]. Accordingly, P 4 and progestins decrease the expression of TGFβ target genes SMAD, P38, NFKBP, RAS, and PI3K [ 91 ]. The inhibition of TGFβ production by high-dose P 4 is associated with a decrease in phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling since this pathway is activated by TGFβ.…”

Section: Progesterone Regulates T-cell Activation and Cytokine Produc...mentioning

confidence: 99%

“…The inhibition of TGFβ production by high-dose P 4 is associated with a decrease in phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling since this pathway is activated by TGFβ. There is evidence indicating that the inhibition of the TGFβ signaling pathway may be beneficial in autoimmune disorders, such as multiple sclerosis, through the downregulation of the TH17 pathway [ 89 , 91 ].…”

Section: Progesterone Regulates T-cell Activation and Cytokine Produc...mentioning

confidence: 99%

“…P 4 also demonstrated a unique action on mitochondria [ 91 ]; thus, considering the expression of FKBP51, together with the finding that mitochondrial PR also exists in mitochondria [ 138 ], the translocation of FKBP51 from the mitochondria to the nucleus may have great importance. Hsp90 inhibitors favor FKBP51 translocation from the mitochondria to the nucleus in a reversible manner.…”

Section: New Aspects In the Application Of Progesterone And Progester...mentioning

confidence: 99%

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Progesterone as an Anti-Inflammatory Drug and Immunomodulator: New Aspects in Hormonal Regulation of the Inflammation

Федотчева

Shimanovsky

2022

Biomolecules

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The specific regulation of inflammatory processes by steroid hormones has been actively studied in recent years, especially by progesterone (P4) and progestins. The mechanisms of the anti-inflammatory and immunomodulatory P4 action are not fully clear. The anti-inflammatory effects of P4 can be defined as nonspecific, associated with the inhibition of NF-κB and COX, as well as the inhibition of prostaglandin synthesis, or as specific, associated with the regulation of T-cell activation, the regulation of the production of pro- and anti-inflammatory cytokines, and the phenomenon of immune tolerance. The specific anti-inflammatory effects of P4 and its derivatives (progestins) can also include the inhibition of proliferative signaling pathways and the antagonistic action against estrogen receptor beta-mediated signaling as a proinflammatory and mitogenic factor. The anti-inflammatory action of P4 is accomplished through the participation of progesterone receptor (PR) chaperones HSP90, as well as immunophilins FKBP51 and FKBP52, which are the validated targets of clinically approved immunosuppressive drugs. The immunomodulatory and anti-inflammatory effects of HSP90 inhibitors, tacrolimus and cyclosporine, are manifested, among other factors, due to their participation in the formation of an active ligand–receptor complex of P4 and their interaction with its constituent immunophilins. Pharmacological agents such as HSP90 inhibitors can restore the lost anti-inflammatory effect of glucocorticoids and P4 in chronic inflammatory and autoimmune diseases. By regulating the activity of FKBP51 and FKBP52, it is possible to increase or decrease hormonal signaling, as well as restore it during the development of hormone resistance. The combined action of immunophilin suppressors with steroid hormones may be a promising strategy in the treatment of chronic inflammatory and autoimmune diseases, including endometriosis, stress-related disorders, rheumatoid arthritis, and miscarriages. Presumably, the hormone receptor- and immunophilin-targeted drugs may act synergistically, allowing for a lower dose of each.

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Section: Progesterone Regulates T-cell Activation and Cytokine Produc...mentioning

confidence: 99%

Section: Progesterone Regulates T-cell Activation and Cytokine Produc...mentioning

confidence: 99%

Section: New Aspects In the Application Of Progesterone And Progester...mentioning

confidence: 99%

See 1 more Smart Citation

Progesterone as an Anti-Inflammatory Drug and Immunomodulator: New Aspects in Hormonal Regulation of the Inflammation

Федотчева

Shimanovsky

2022

Biomolecules

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“…SMAD7 is an antagonist of TGF-β1 signaling and complexes with the TGF-βRI to inhibit downstream signaling and pro-tumorigenic transcriptional activation. Proteins that regulate SMAD7 activity act to attenuate TGF-β1-mediated aggressive phenotypes in breast cancer ( Hu et al, 2021 ). In colon cancer, SMAD7 deletion predisposes to a favorable prognosis, while SMAD7 amplification is linked to poor outcomes ( Boulay et al, 2003 ).…”

Section: Role Of Tgf−β Signaling In Cancermentioning

confidence: 99%

Targeting TGF-β signaling in the multiple myeloma microenvironment: Steering CARs and T cells in the right direction

Rana

Soler

Kort

et al. 2022

Front. Cell Dev. Biol.

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Multiple myeloma (MM) remains a lethal hematologic cancer characterized by the expansion of transformed plasma cells within the permissive bone marrow (BM) milieu. The emergence of relapsed and/or refractory MM (RRMM) is provoked through clonal evolution of malignant plasma cells that harbor genomic, metabolic and proteomic perturbations. For most patients, relapsed disease remains a major cause of overall mortality. Transforming growth factors (TGFs) have pleiotropic effects that regulate myelomagenesis as well as the emergence of drug resistance. Moreover, TGF-β modulates numerous cell types present with the tumor microenvironment, including many immune cell types. While numerous agents have been FDA-approved over the past 2 decades and significantly expanded the treatment options available for MM patients, the molecular mechanisms responsible for drug resistance remain elusive. Multiple myeloma is uniformly preceded by a premalignant state, monoclonal gammopathy of unknown significance, and both conditions are associated with progressive deregulation in host immunity characterized by reduced T cell, natural killer (NK) cell and antigen-presenting dendritic cell (DC) activity. TGF-β promotes myelomagenesis as well as intrinsic drug resistance by repressing anti-myeloma immunity to promote tolerance, drug resistance and disease progression. Hence, repression of TGF-β signaling is a prerequisite to enhance the efficacy of current and future immunotherapeutics. Novel strategies that incorporate T cells that have been modified to express chimeric antigen receptor (CARs), T cell receptors (TCRs) and bispecific T cell engagers (BiTEs) offer promise to block TGF-β signaling, overcome chemoresistance and enhance anti-myeloma immunity. Here, we describe the effects of TGF-β signaling on immune cell effectors in the bone marrow and emerging strategies to overcome TGF-β-mediated myeloma growth, drug resistance and survival.

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“…This homeostasis depends on the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), which are the key factors in the degradation and remodeling of the ECM. TGF-β1 is a pivotal profibrogenic cytokine in liver fibrosis and an inhibitor of hepatocyte proliferation that can induce small mothers against decapentaplegic (Smad) 2/3 transcription and activate HSCs but is negatively regulated by Smad 7 [ 100 , 101 , 102 , 103 ]. In addition, the serum indexes of type III procollagen (PC-III), Col-IV, laminin (LN), and hyaluronidase (HA) can effectively reflect the condition of liver injury and fibrosis, and they are commonly used as clinical indicators to reflect liver fibrosis.…”

Section: Pe Improves Liver Fibrosis and Collagen Depositionmentioning

confidence: 99%

Protective Effect and Mechanism of Placenta Extract on Liver

et al. 2022

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The placenta contains multiple biologically active substances, which exert antioxidation, anti-inflammatory, immunomodulatory, and delayed aging effects. Its extract can improve hepatic morphology and function: on the one hand, it can reduce liver interstitial collagen deposition, lipogenesis, and inflammatory cell infiltration and improve fibrosis; on the other hand, it can prevent hepatocellular degeneration by scavenging reactive oxygen species (ROS) and inhibiting inflammatory cytokine production, further improve hepatocyte apoptosis and necrosis, and promote hepatocyte regeneration, making it a promising liver-protective agent. Current research on placenta extract (PE) mainly focuses on treating a specific type of liver injury, and there are no systematic reports. Therefore, this review comprehensively summarizes the treatment reports of PE on liver injury and analyzes its mechanism of action.

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Expression and function of Smad7 in autoimmune and inflammatory diseases

Cited by 22 publications

References 110 publications

Progesterone as an Anti-Inflammatory Drug and Immunomodulator: New Aspects in Hormonal Regulation of the Inflammation

Progesterone as an Anti-Inflammatory Drug and Immunomodulator: New Aspects in Hormonal Regulation of the Inflammation

Targeting TGF-β signaling in the multiple myeloma microenvironment: Steering CARs and T cells in the right direction

Protective Effect and Mechanism of Placenta Extract on Liver

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