scholarly journals Targeting of Janus Kinases Limits Pro-Inflammatory but Also Immunosuppressive Circuits in the Crosstalk between Synovial Fibroblasts and Lymphocytes

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1413
Author(s):  
Nina Yao ◽  
Theresa Tretter ◽  
Peter Kvacskay ◽  
Wolfgang Merkt ◽  
Norbert Blank ◽  
...  
Keyword(s):  
Immune Cells ◽  
Kinase Inhibitors ◽  
Synergistic Effects ◽  
Synovial Fibroblasts ◽  
Janus Kinase ◽  
Response To Treatment ◽  
Th Cells ◽  
Proven Efficacy ◽  
Clinical Responses

Crosstalk between synovial fibroblasts (SF) and immune cells plays a central role in the development of rheumatoid arthritis (RA). Janus kinase inhibitors (JAKi) have proven efficacy in the treatment of RA, although clinical responses are heterogeneous. Currently, little is known regarding how JAKi affect pro- and anti-inflammatory circuits in the bidirectional interplay between SF and immune cells. Here, we examined the effects of tofacitinib, baricitinib and upadacitinib on crosstalk between SF and T or B lymphocytes in vitro and compared them with those of biologic disease modifying anti-rheumatic drugs (bDMARDs). JAKi dose-dependently suppressed cytokine secretion of T helper (Th) cells and decreased interleukin (IL)-6 and matrix metalloproteinase (MMP)3 secretion of SF stimulated by Th cells. Importantly, JAK inhibition attenuated the enhanced memory response of chronically stimulated SF. Vice versa, JAKi reduced the indoleamine-2,3-dioxygenase (IDO)1-mediated suppression of T cell-proliferation by SF. Remarkably, certain bDMARDs were as efficient as JAKi in suppressing the IL-6 and MMP3 secretion of SF stimulated by Th (adalimumab, secukinumab) or B cells (canakinumab) and combining bDMARDs with JAKi had synergistic effects. In conclusion, JAKi limit pro-inflammatory circuits in the crosstalk between SF and lymphocytes; however, they also weaken the immunosuppressive functions of SF. Both effects were dose-dependent and may contribute to heterogeneity in clinical response to treatment.

scholarly journals Clinical management of Lupus patients during the COVID-19 pandemic

Lupus ◽  
2020 ◽  
Vol 29 (13) ◽  
pp. 1661-1672
Author(s):  
Alice Mason ◽  
Emily Rose ◽  
Christopher J Edwards
Keyword(s):  
Kinase Inhibitors ◽  
Viral Infections ◽  
Positive Impact ◽  
Severe Disease ◽  
Social Contact ◽  
Janus Kinase ◽  
Current Evidence ◽  
Janus Kinase Inhibitors ◽  
Huge Impact

Severe acute respiratory syndrome coronavirus (SARS-CoV-2), the virus causing Coronavirus disease 2019 (COVID-19), has had a huge impact on health services with a high mortality associated with complications including pneumonia and acute respiratory distress syndrome. Historical evidence suggests that Lupus patients have a higher incidence of several viral infections. This is likely due to a combination of immune dysfunction, immunosuppressive therapy and excess co-morbidities. In this context there has been concern that Lupus patients may be at a higher risk of developing COVID-19 and suffering a severe disease course. As a result, many Lupus patients have been advised to ‘shield’ by isolating from social contact in the hope that this will reduce the likelihood of infection. Early clinical data does not appear to show that the incidence of COVID-19 is higher in Lupus patients. Reassuringly, the clinical course of COVID-19 in Lupus does not generally seem to be more severe than in the general population. There has been huge interest in repurposing existing drugs as potential treatments, including several used to treat Lupus. Of these, corticosteroids and hydroxychloroquine are the most well researched so far. The current evidence suggests that the corticosteroid dexamethasone improves outcome for the sickest COVID-19 patients requiring respiratory support. Initial reports suggested that hydroxychloroquine could have a positive impact on the course of COVID-19, however larger prospective studies have not supported this. Janus kinase inhibitors, currently being investigated for efficacy in lupus, have been shown to have anti-viral effects in vitro and inhibiting the JAK-STAT pathway may dampen down the host hyper-inflammatory response. Several trials are ongoing to assess the outcome of the use of JAK inhibitors in COVID-19 positive patients. For most patients continuing with their existing therapies to prevent a lupus flare or adverse events associated with sudden corticosteroid withdrawal is important whilst an Individualised risk assessment remains vital.

The Relevance of Aurora Kinase Inhibition in Hematological Malignancies

2021 ◽  
Vol 1 (3) ◽  
pp. 111-126
Author(s):  
CAIO BEZERRA MACHADO ◽  
EMERSON LUCENA DA SILVA ◽  
BEATRIZ MARIA DIAS NOGUEIRA ◽  
JEAN BRENO SILVEIRA DA SILVA ◽  
MANOEL ODORICO DE MORAES FILHO ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Hematological Malignancies ◽  
Kinase Inhibitors ◽  
Synergistic Effects ◽  
Aurora Kinase ◽  
Aurora Kinases ◽  
The Past ◽  
Oncologic Patients

Aurora kinases are a family of serine/threonine protein kinases that play a central role in eukaryotic cell division. Overexpression of aurora kinases in cancer and their role as major regulators of the cell cycle quickly inspired the idea that their inhibition might be a potential pathway when treating oncologic patients. Over the past couple of decades, the search for designing and testing of molecules capable of inhibiting aurora activities fueled many pre-clinical and clinical studies. In this study, data from the past 10 years of in vitro and in vivo investigations, as well as clinical trials, utilizing aurora kinase inhibitors as therapeutics for hematological malignancies were compiled and discussed, aiming to highlight potential uses of these inhibitors as a novel monotherapy model or alongside conventional chemotherapies. While there is still much to be elucidated, it is clear that these kinases play a key role in oncogenesis, and their manageable toxicity and potentially synergistic effects still render them a focus of interest for future investigations in combinatorial clinical trials

scholarly journals Sorafenib and Mek inhibition is synergistic in medullary thyroid carcinoma in vitro

2011 ◽  
Vol 19 (1) ◽  
pp. 29-38 ◽  
Author(s):  
Yoon Woo Koh ◽  
Manisha H Shah ◽  
Kitty Agarwal ◽  
Samantha K McCarty ◽  
Bon Seok Koo ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Synergistic Effects ◽  
Mek Inhibitor ◽  
Parp Cleavage ◽  
Mechanisms Of Resistance ◽  
Multikinase Inhibitor ◽  
Western Blots ◽  
Medullary Thyroid ◽  
Base Compound

Clinical trials using kinase inhibitors have demonstrated transient partial responses and disease control in patients with progressive medullary thyroid cancer (MTC). The goal of this study was to identify potential combinatorial strategies to improve on these results using sorafenib, a multikinase inhibitor with activity in MTC, as a base compound to explore signaling that might predict synergystic interactions. Two human MTC cell lines, TT and MZ-CRC-1, which harbor endogenous C634W or M918T RET mutations, respectively, were exposed to sorafenib, everolimus, and AZD6244 alone and in combination. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide (MTT) and poly (ADP-ribose) polymerase (PARP) cleavage assays were performed to measure cell survival and apoptosis. Western blots were performed to confirm activity of the compounds and to determine possible mechanisms of resistance and predictors of synergy. As a solitary agent, sorafenib was the most active compound on MTT assay. Western blots confirmed that sorafenib, everolimus, and AZD6244 inhibited their anticipated targets. At concentrations below its IC50, sorafenib-treated TT and MZ-CRC-1 cells demonstrated transient inhibition and then re-activation of Erk over 6 h. In concordance, synergistic effects were only identified using sorafenib in combination with the Mek inhibitor AZD6244 (P<0.001 for each cell line). Cells treated with everolimus demonstrated activation of Akt and Ret via TORC2 complex-dependent and TORC2 complex-independent mechanisms respectively. Everolimus was neither additive nor syngergistic in combination with sorafenib or AZD6244. In conclusion, sorafenib combined with a Mek inhibitor demonstrated synergy in MTC cells in vitro. Mechanisms of resistance to everolimus in MTC cells likely involved TORC2-dependent and TORC2-independent pathways.

scholarly journals Increased IL-2 and Reduced TGF-β Upon T-Cell Stimulation are Associated with GM-CSF Upregulation in Multiple Immune Cell Types in Multiple Sclerosis

Biomedicines ◽  
2020 ◽  
Vol 8 (7) ◽  
pp. 226
Author(s):  
Jehan Aram ◽  
Nanci Frakich ◽  
Elena Morandi ◽  
Mohammed Alrouji ◽  
Amal Samaraweera ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cell ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Immune Cell ◽  
Interleukin 17 ◽  
Th Cells ◽  
Pbmc Culture ◽  
Gm Csf

Granulocyte macrophage colony stimulating factor (GM-CSF) is a pro-inflammatory cytokine produced by immune cells. Recent evidence suggests that GM-CSF plays an important role in multiple sclerosis (MS) pathogenesis. We investigated the expression and regulation of GM-CSF in different immune cells in MS. We also investigated the differentiation and frequency of GM-CSF-producing Th cells that do not co-express interferon (IFN)-γ or interleukin-17 (IL-17) (Th-GM cells) in MS. We found a significant increase in the percentage of GM-CSF-expressing Th cells, Th1 cells, Th-GM cells, cytotoxic T (Tc) cells, monocytes, natural killer (NK) cells, and B cells in PBMC from MS patients stimulated with T cell stimuli. Stimulated PBMC culture supernatants from MS patients contained significantly higher levels of IL-2, IL-12, IL-1β, and GM-CSF and significantly lower levels of transforming growth factor (TGF-)β. Blocking IL-2 reduced the frequency of Th-GM cells in PBMC from MS patients. The frequency of Th-GM cells differentiated in vitro from naïve CD4+ T cells was significantly higher in MS patients and was further increased in MS with IL-2 stimulation. These findings suggest that all main immune cell subsets produce more GM-CSF in MS after in vitro stimulation, which is associated with defective TGF-β and increased IL-2 and IL-12 production. Th-GM cells are increased in MS. GM-CSF may be a potential therapeutic target in MS.

Expression of the JAK and STAT superfamilies in human meningiomas

1999 ◽  
Vol 91 (3) ◽  
pp. 440-446 ◽  
Author(s):  
Lorenzo Magrassi ◽  
Claudio De-Fraja ◽  
Luciano Conti ◽  
Giorgio Butti ◽  
Lodovico Infuso ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Signal Transduction Pathway ◽  
Janus Kinase ◽  
Response To Treatment ◽  
Interferon Α ◽  
Content Type ◽  
Human Meningiomas ◽  
Fine Print

Object. The goal of this study was to investigate whether the janus kinase/signal transducer and activator of transcription (JAK/STAT) signal transduction pathway is present and active in meningiomas. The results of these investigations are important for all meningioma therapies that, similar to interferon-α-2B (IFNα-2B), depend on activation of this pathway for their effect. The authors were interested in evaluating the importance, if any, of the JAK/STAT pathway in the biology and therapy for these tumors.Methods. Total proteins were extracted from 17 meningioma samples and the levels of JAKs and STATs were determined by using Western blot analysis. Levels of these proteins in meningiomas were compared with those found in normal dura. The JAKs and STATs (with the exception of Jak3 and Tyk2) were present both in the dura and in the meningiomas studied. In tumors JAK and STAT levels were always significantly higher than those found in normal dura. Differences in relative levels were found when meningiomas were subdivided according to the current neuropathological criteria and the highest levels were found in transitional meningiomas. The authors also investigated, using tyrosine-phosphorylated Stat1 and Stat3 antibodies, whether STATs were activated in meningiomas and normal dura in vivo. Their results indicate that both Stat1 and Stat3 are phosphorylated in vivo in meningiomas and in the dura. Furthermore, in vitro experiments in which two independent short-term cultures obtained from freshly dissected meningioma samples were used indicated that Stat1 and Stat3 are phosphorylated in response to treatment with IFNα-2B. Exposure of meningioma cells to IFNα-2B leads to nuclear translocation of tyrosine-phosphorylated Stat1 and Stat3, as demonstrated by immunocytochemical analysis.Conclusions. The results of this study indicate that the JAK and STAT families of proteins are important effectors in brain tumors and support the idea that the effects of IFNα in vivo are direct and not mediated by the immune system. This suggests a role for modulation of STAT transcription factors in inhibiting meningioma cell proliferation.

scholarly journals The Era of Janus Kinase Inhibitors for Inflammatory Bowel Disease Treatment

2021 ◽  
Vol 22 (21) ◽  
pp. 11322
Author(s):  
Jin-Woo Kim ◽  
Su-Young Kim
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Kinase Inhibitors ◽  
Significant Proportion ◽  
Janus Kinase ◽  
Response To Treatment ◽  
Interleukin 12 ◽  
Disease Treatment ◽  
Janus Kinase Inhibitors ◽  
Inflammatory Bowel

For a significant proportion of patients with inflammatory bowel disease (IBD), primary non-response and secondary loss of response to treatment remain significant issues. Anti-tumor necrosis factor therapies have been licensed for use in IBD. Other disease-related pathways have been targeted as well, including the interleukin 12/23 axis and lymphocyte tracking. However, the need for parenteral administration and the associated costs of dispensing and monitoring all biologics remain a burden on healthcare systems and patients. Janus kinase inhibitors are small-molecule drugs that can be administered orally and are relatively inexpensive, thus offering an additional option for treating IBD. They have been shown to be effective in patients with ulcerative colitis (UC), but they are less effective in those with Crohn’s disease (CD). Nonetheless, given the immune-system-based mechanism of these drugs, their safety profile remains a cause for concern. This article provides an overview of Janus kinase (JAK) inhibitors and new trends in the treatment of IBD.

scholarly journals The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-γ production in T cells from patients with SLE

2018 ◽  
Vol 77 (7) ◽  
pp. 1070-1077 ◽  
Author(s):  
Niklas Hagberg ◽  
Martin Joelsson ◽  
Dag Leonard ◽  
Sarah Reid ◽  
Maija-Leena Eloranta ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Lupus Erythematosus ◽  
Kinase Inhibitors ◽  
Mononuclear Cells ◽  
Risk Allele ◽  
Severe Disease ◽  
Janus Kinase ◽  
Peripheral Blood Mononuclear ◽  
Ifn Γ

ObjectivesGenetic variants in the transcription factor STAT4 are associated with increased susceptibility to systemic lupus erythematosus (SLE) and a more severe disease phenotype. This study aimed to clarify how the SLE-associated intronic STAT4 risk allele rs7574865[T] affects the function of immune cells in SLE.MethodsPeripheral blood mononuclear cells (PBMCs) were isolated from 52 genotyped patients with SLE. Phosphorylation of STAT4 (pSTAT4) and STAT1 (pSTAT1) in response to interferon (IFN)-α, IFN-γ or interleukin (IL)-12, total levels of STAT4, STAT1 and T-bet, and frequency of IFN-γ+ cells on IL-12 stimulation were determined by flow cytometry in subsets of immune cells before and after preactivation of cells with phytohaemagglutinin (PHA) and IL-2. Cellular responses and phenotypes were correlated to STAT4 risk allele carriership. Janus kinase inhibitors (JAKi) selective for TYK2 (TYK2i) or JAK2 (JAK2i) were evaluated for inhibition of IL-12 or IFN-γ-induced activation of SLE PBMCs.ResultsIn resting PBMCs, the STAT4 risk allele was neither associated with total levels of STAT4 or STAT1, nor cytokine-induced pSTAT4 or pSTAT1. Following PHA/IL-2 activation, CD8+ T cells from STAT4 risk allele carriers displayed increased levels of STAT4 resulting in increased pSTAT4 in response to IL-12 and IFN-α, and an augmented IL-12-induced IFN-γ production in CD8+ and CD4+ T cells. The TYK2i and the JAK2i efficiently blocked IL-12 and IFN-γ-induced activation of PBMCs from STAT4 risk patients, respectively.ConclusionsT cells from patients with SLE carrying the STAT4 risk allele rs7574865[T] display an augmented response to IL-12 and IFN-α. This subset of patients may benefit from JAKi treatment.

scholarly journals Impact of Different JAK Inhibitors and Methotrexate on Lymphocyte Proliferation and DNA Damage

2021 ◽  
Vol 10 (7) ◽  
pp. 1431
Author(s):  
Annika Reddig ◽  
Linda Voss ◽  
Karina Guttek ◽  
Dirk Roggenbuck ◽  
Eugen Feist ◽  
...  
Keyword(s):  
Dna Damage ◽  
Lymphocyte Proliferation ◽  
Kinase Inhibitors ◽  
Mononuclear Cells ◽  
In Vitro Study ◽  
Janus Kinase ◽  
European Medicines Agency ◽  
Peripheral Blood Mononuclear ◽  
Dose Dependent

Janus kinase inhibitors (JAKis) represent a new strategy in rheumatoid arthritis (RA) therapy. Still, data directly comparing different JAKis are rare. In the present in vitro study, we investigated the immunomodulatory potential of four JAKis (tofacitinib, baricitinib, upadacitinib, and filgotinib) currently approved for RA treatment by the European Medicines Agency. Increasing concentrations of JAKi or methotrexate, conventionally used in RA therapy, were either added to freshly mitogen-stimulated or preactivated peripheral blood mononuclear cells (PBMC), isolated from healthy volunteers. A comparable, dose-dependent inhibition of lymphocyte proliferation was observed in samples treated with tofacitinib, baricitinib, and upadacitinib, while dosage of filgotinib had to be two orders of magnitude higher. In contrast, antiproliferative effects were strongly attenuated when JAKi were added to preactivated PBMCs. High dosage of upadacitinib and filgotinib also affected cell viability. Further, analyses of DNA double-strand break markers γH2AX and 53BP1 indicated an enhanced level of DNA damage in cells incubated with high concentrations of filgotinib and a dose-dependent reduction in clearance of radiation-induced γH2AX foci in the presence of tofacitinib or baricitinib. Thereby, our study demonstrated a broad comparability of immunomodulatory effects induced by different JAKi and provided first indications, that (pan)JAKi may impair DNA damage repair in irradiated PBMCs.

Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors

Blood ◽  
2004 ◽  
Vol 103 (10) ◽  
pp. 3736-3743 ◽  
Author(s):  
Brian J. Lannutti ◽  
Jonathan G. Drachman
Keyword(s):  
Cellular Proliferation ◽  
Kinase Inhibitors ◽  
Dominant Negative ◽  
Janus Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activity ◽  
Targeted Mutation ◽  
Mitogen Activated Protein ◽  
Nuclear Ploidy

Abstract In this study we demonstrate that thrombopoietin (TPO)–stimulated Src family kinases (SFKs) inhibit cellular proliferation and megakaryocyte differentiation. Using the Src kinase inhibitors pyrolopyrimidine 1 and 2 (PP1, PP2), we show that TPO-dependent proliferation of BaF3/Mpl cells was enhanced at concentrations that are specific for SFKs. Similarly, proliferation is increased after introducing a dominant-negative form of Lyn into BaF3/Mpl cells. Murine marrow cells from Lyn-deficient mice or wild-type mice cultured in the presence of the Src inhibitor, PP1, yielded a greater number of mature megakaryocytes and increased nuclear ploidy. Truncation and targeted mutation of the Mpl cytoplasmic domain indicate that Y112 is critical for Lyn activation. Examining the molecular mechanism for this antiproliferative effect, we determined that SFK inhibitors did not affect tyrosine phosphorylation of Janus kinase 2 (JAK2), Shc, signal transducer and activator of transcription (STAT)5, or STAT3. In contrast, pretreatment of cells with PP2 increased Erk1/2 (mitogen-activated protein kinase [MAPK]) phosphorylation and in vitro kinase activity, particularly after prolonged TPO stimulation. Taken together, our results show that Mpl stimulation results in the activation of Lyn kinase, which appears to limit the proliferative response through a signaling cascade that regulates MAPK activity. These data suggest that SFKs modify the rate of TPO-induced proliferation and are likely to affect cell cycle regulation during megakaryocytopoiesis.

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