CDK inhibitors suppress Th17 and promote iTreg differentiation, and ameliorate experimental autoimmune encephalomyelitis in mice

Yoshida, Hideyuki; Kotani, Hitoshi; Kondo, Taisuke; Tani, Ito; Wei, Xuetao; Tsuruta, Sanae; Kimura, Akihiro; Asakawa, Mayako; Ito, Minako; Nagai, Shigenori; Yoshimura, Akihiko

doi:10.1016/j.bbrc.2013.04.096

Cited by 19 publications

(13 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Substrate specificity is determined by the L3 loop in the MH2 domain of R-Smads and the L45 loop in TGF-β type I receptors [23,25]. R-Smad phosphorylation can also be negatively modulated by cyclin-dependent kinase, p38 MAP kinase, JNK kinase, TGF β-activated kinase-1, protein kinase C, MpS1 (MonoPolar Spindle 1) protein kinases, G-protein-coupled receptor kinase-2, and calcium/ calmodulin-dependent protein kinase II (CAMKII)-which occurs in the MH1 domain and the linker region [17,21,[26][27][28][29][30][31]. Many Ste20 (Sterile 20) protein kinases have been suggested to act as MAP4Ks (MAP kinase kinase kinase kinases) upstream of MAP kinases, and they were found to be able to block C-terminal phosphorylation of specific R-Smads (Smad1, 2, 5 and 8), through a single highly conserved phosphorylation event in the MH2 domain (α-helix 1: T322 in Smad1/5/8 and T324 in Smad2) [32].…”

Section: Regulation Of R-smadsmentioning

confidence: 99%

Role of Smad signaling in kidney disease

et al. 2015

View full text Add to dashboard Cite

Smads are the key intermediates of canonical transforming growth factor-beta (TGF-β) signaling. These intermediates are divided into three distinct subgroups based on their role in TGF-β family signal transduction: Receptor-regulated Smads (R-Smads) 1, 2, 3, 5 and 8, common Smad4, and inhibitory Smads6 and 7. TGF-β signaling through Smad pathway involves phosphorylation, ubiquitination, sumoylation, acetylation, and protein-protein interactions with mitogen-activated protein kinases, PI3K-Akt/PKB, and Wnt/GSK-3. Several studies have suggested that upregulation or downregulation of TGF-β/Smad signaling pathways may be a pathogenic mechanism in the progression of chronic kidney disease. Smad2 and 3 are the two major downstream R-Smads in TGF-β-mediated renal fibrosis, while Smad7 also controls renal inflammation. In this review, we characterize the role of Smads in kidney disease, describe the molecular mechanisms, and discuss the potential of Smads as a therapeutic target in chronic kidney disease.

show abstract

Section: Regulation Of R-smadsmentioning

confidence: 99%

Role of Smad signaling in kidney disease

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Several articles have described the effects of roscovitine on T lymphocytes [207–209]. A screen of 256 inhibitors of intracellular signaling pathways has led to the identification of CDK inhibitors, and roscovitine in particular, as suppressors of Th17 differentiation and, thus, as activators of iTregs differentiation [207].…”

Section: Roscovitine and Cystic Fibrosismentioning

confidence: 99%

“…A screen of 256 inhibitors of intracellular signaling pathways has led to the identification of CDK inhibitors, and roscovitine in particular, as suppressors of Th17 differentiation and, thus, as activators of iTregs differentiation [207]. Induction of iTreg cell differentiation by CDK2 inhibition was recently confirmed with kenpaullone, another pharmacological inhibitor of CDKs [210].…”

Section: Roscovitine and Cystic Fibrosismentioning

confidence: 99%

“…As roscovitine is also a DYRK1A inhibitor (IC 50 in the μM range) [212, 34], its effect on DYRK1A may contribute to its effects on T cell differentiation. In a mouse model, roscovitine suppresses experimental autoimmune encephalomyelitis (EAE), an auto-immune disease mediated by Th17 cells [207]. Roscovitine suppresses CD4+ T helper (Th) cells and has a beneficial effect on a uveitis mouse model, an auto-immune disease [208].…”

Section: Roscovitine and Cystic Fibrosismentioning

confidence: 99%

See 1 more Smart Citation

Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis

et al. 2016

View full text Add to dashboard Cite

(R)-Roscovitine, a pharmacological inhibitor of kinases, is currently in phase II clinical trial as a drug candidate for the treatment of cancers, Cushing's disease and rheumatoid arthritis. We here review the data that support the investigation of (R)-roscovitine as a potential therapeutic agent for the treatment of cystic fibrosis (CF). (R)-Roscovitine displays four independent properties that may favorably combine against CF: (1) it partially protects F508del-CFTR from proteolytic degradation and favors its trafficking to the plasma membrane; (2) by increasing membrane targeting of the TRPC6 ion channel, it rescues acidification in phagolysosomes of CF alveolar macrophages (which show abnormally high pH) and consequently restores their bactericidal activity; (3) its effects on neutrophils (induction of apoptosis), eosinophils (inhibition of degranulation/induction of apoptosis) and lymphocytes (modification of the Th17/Treg balance in favor of the differentiation of anti-inflammatory lymphocytes and reduced production of various interleukins, notably IL-17A) contribute to the resolution of inflammation and restoration of innate immunity, and (4) roscovitine displays analgesic properties in animal pain models. The fact that (R)-roscovitine has undergone extensive preclinical safety/pharmacology studies, and phase I and II clinical trials in cancer patients, encourages its repurposing as a CF drug candidate.

show abstract

“…Inhibition of CDK7 suppressed LPS-induced NO production through inhibiting/NF-jB activation in macrophages [13]. CDK inhibitors suppress Th17 and promote iTreg differentiation, and ameliorate experimental autoimmune encephalomyelitis in mice [14]. However, the role of CDK7 in RA remains to be explored.…”

Section: Introductionmentioning

confidence: 98%

Selective inhibition of CDK7 ameliorates experimental arthritis in mice

et al. 2014

View full text Add to dashboard Cite

Cyclin-dependent kinases (CDKs) have emerged as anti-inflammatory targets. The purpose of this study was to explore the therapeutic effects of a selective CDK7 inhibitor, BS-181, on mice with established collagen-induced arthritis (CIA). CIA mice were administered intraperitoneally with BS-181 (10 mg/kg) twice daily for 2 weeks. Control mice received vehicle only. Arthritis severity and joint histopathology were examined. The proinflammatory cytokines and anti-type II collagen antibodies (anti-CII) were determined by ELISA. IkB kinase (IKK)-β/NF-κB activation in the arthritic joints was assessed by Western blot. The ratio of Th17 cells was determined by flow cytometry. In vitro, splenocytes from mice with established CIA were stimulated with CII in the presence or absence of BS-181 and cytokines were detected. BS-181 treatment reduced the clinical score and histological damage in CIA mice. The serum proinflammatory cytokines (IL-6, IL-1β and IL-17) and anti-CII IgG2a levels were also decreased by BS-181 administration. Moreover, IKK-β/NF-κB signaling pathway was inhibited in arthritic joints. BS-181 administration also decreased the ratio of Th17 cells. In addition, CIA splenocytes pretreated with BS-181 produced less proinflammatory cytokines in vitro. These findings indicate that CDK7 inhibition by BS-181 is effective in the treatment of CIA, which might be mediated by suppression of IKK-β/NF-κB activation and Th17 cell response.

show abstract

CDK inhibitors suppress Th17 and promote iTreg differentiation, and ameliorate experimental autoimmune encephalomyelitis in mice

Cited by 19 publications

References 37 publications

Role of Smad signaling in kidney disease

Role of Smad signaling in kidney disease

Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis

Selective inhibition of CDK7 ameliorates experimental arthritis in mice

Contact Info

Product

Resources

About