Tofacitinib Suppresses Several JAK-STAT Pathways in Rheumatoid Arthritis In Vivo and Baseline Signaling Profile Associates With Treatment Response

Palmroth, Maaria; Kuuliala, Krista; Peltomaa, Ritva; Virtanen, Anniina; Kuuliala, Antti; Kurttila, Antti; Kinnunen, Anna; Leirisalo‐Repo, Marjatta; Silvennoinen, Olli; Isomäki, Pia

doi:10.3389/fimmu.2021.738481

Cited by 33 publications

(16 citation statements)

References 41 publications

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“…Several JAK inhibitors such as Ruxolitinib, Tofacitinib, Baricitinib, and Upadacitinib have been approved for the treatment of chronic inflammatory and myeloproliferative diseases (67)(68)(69)(70)(71)(72). However, the clinical benefit of these JAK inhibitors had been largely restricted due to the potential safety risks.…”

Section: Discussionmentioning

confidence: 99%

“…These developments support the investigation of a wide dose range in clinical trials without elevating the risk of off-target toxicity owing to other related kinase activities, particularly the JAK family kinases. Traditionally designed JAK kinase inhibitors that target JAK catalytic site, such as Ruxolitinib (pan JAK kinase inhibitor) (16,68) and Tofacitinib (JAK1/JAK3 dual inhibitor with little selectivity over JAK2) (69,70) were designed to target the ATP binding site in catalytic domain and show poor selectivity within the JAK family (16,21,27) (Supplementary Figure 1). This is largely due to the nature of the high homology within the active site of JAK kinase family.…”

Section: Discussionmentioning

confidence: 99%

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Novel Small Molecule Tyrosine Kinase 2 Pseudokinase Ligands Block Cytokine-Induced TYK2-Mediated Signaling Pathways

Zhou

Shen

et al. 2022

Front. Immunol.

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A member of the Janus kinase (JAK) family, Tyrosine Kinase 2 (TYK2), is crucial in mediating various cytokine-signaling pathways such as interleukin-23 (IL23), interleukin-12 (IL12) and type I Interferons (IFN) which contribute to autoimmune disorders (e.g., psoriasis, lupus, and inflammatory bowel disease). Thus, TYK2 represents an attractive target to develop small-molecule therapeutics for the treatment of cytokine-driven inflammatory diseases. Selective inhibition of TYK2 over other JAK isoforms is critical to achieve a favorable therapeutic index in the development of TYK2 inhibitors. However, designing small molecule inhibitors to target the adenosine triphosphate (ATP) binding site of TYK2 kinase has been challenging due to the substantial structural homology of the JAK family catalytic domains. Here, we employed an approach to target the JAK homology 2 (JH2) pseudokinase regulatory domain of the TYK2 protein. We developed a series of small-molecule TYK2 pseudokinase ligands, which suppress the TYK2 catalytic activity through allosteric regulation. The TYK2 pseudokinase-binding small molecules in this study simultaneously achieve high affinity-binding for the TYK2 JH2 domain while also affording significantly reduced affinity for the TYK2 JAK homology 1 (JH1) kinase domain. These TYK2 JH2 selective molecules, although possessing little effect on suppressing the catalytic activity of the isolated TYK2 JH1 catalytic domain in the kinase assays, can still significantly block the TYK2-mediated receptor-stimulated pathways by binding to the TYK2 JH2 domain and allosterically regulating the TYK2 JH1 kinase. These compounds are potent towards human T-cell lines and primary immune cells as well as in human whole-blood specimens. Moreover, TYK2 JH2-binding ligands exhibit remarkable selectivity of TYK2 over JAK isoforms not only biochemically but also in a panel of receptor-stimulated JAK1/JAK2/JAK3-driven cellular functional assays. In addition, the TYK2 JH2-targeting ligands also demonstrate high selectivity in a multi-kinase screening panel. The data in the current study underscores that the TYK2 JH2 pseudokinase is a promising therapeutic target for achieving a high degree of biological selectivity. Meanwhile, targeting the JH2 domain represents an appealing strategy for the development of clinically well-tolerated TYK2 inhibitors that would have superior efficacy and a favorable safety profile compared to the existing Janus kinase inhibitors against autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Novel Small Molecule Tyrosine Kinase 2 Pseudokinase Ligands Block Cytokine-Induced TYK2-Mediated Signaling Pathways

Zhou

Shen

et al. 2022

Front. Immunol.

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“…We did not evaluate the phosphorylation of JAK/STAT factors in our cell cultures following the administration of tofacitinib. However, the inhibition of the phosphorylation of JAK/STAT factors on synovial cells as well as on immune cells following the treatment with tofacitinib has already been demonstrated [ 29 , 30 , 31 ]. On these bases, we focused our work on further possible mechanisms of tofacitinib in RA-FLSs, exploring additional effects of this drug on markers of fibroblast activation.…”

Section: Discussionmentioning

confidence: 99%

Tofacitinib May Inhibit Myofibroblast Differentiation from Rheumatoid-Fibroblast-like Synoviocytes Induced by TGF-β and IL-6

et al. 2022

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During rheumatoid arthritis (RA), the pathogenic role of resident cells within the synovial membrane is suggested, especially for a population frequently referred to as fibroblast-like synoviocytes (FLSs). In this study, we assess the markers of myofibroblast differentiation of RA-FLSs by ex vivo observations and in vitro evaluations following the stimulation with both TGF-β and IL-6. Furthermore, we investigated the possible inhibiting role of tofacitinib, a JAK inhibitor, in this context. Myofibroblast differentiation markers were evaluated on RA synovial tissues by immune-fluorescence or immune-histochemistry. RA-FLSs, stimulated with transforming growth factor (TGF-β) and interleukin-6 (IL-6) with/without tofacitinib, were assessed for myofibroblast differentiation markers expression by qRT-PCR and Western blot. The same markers were evaluated following JAK-1 silencing by siRNA assay. The presence of myofibroblast differentiation markers in RA synovial tissue was significantly higher than healthy controls. Ex vivo, α-SMA was increased, whereas E-Cadherin decreased. In vitro, TGF-β and IL-6 stimulation of RA-FLSs promoted a significant increased mRNA expression of collagen I and α-SMA, whereas E-Cadherin mRNA expression was decreased. In the same conditions, the stimulation with tofacitinib significantly reduced the mRNA expression of collagen I and α-SMA, even if the Western blot did not confirm this finding. JAK-1 gene silencing did not fully prevent the effects of stimulation with TGF-β and IL-6 on these features. TGF-β and IL-6 stimulation may play a role in mediating myofibroblast differentiation from RA-FLSs, promoting collagen I and α-SMA while decreasing E-Cadherin. Following the same stimulation, tofacitinib reduced the increases of both collagen I and α-SMA on RA-FLSs, although further studies are needed to fully evaluate this issue and confirm our results.

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“…It is known that CMCs belong to the first line of immune defense cells and are important antigenpresenting cells recruited to lesion sites during infection or sterile injury and contribute to autoimmune disease development (7,(29)(30)(31). However, disease-specific monocyte populations with unique functions and signatures remain largely unknown.…”

Section: Effect Of Tofa Treatment On Inflammation-and Jak-associated ...mentioning

confidence: 99%

Insights gained from single-cell analysis of immune cells in tofacitinib treatment of Vogt-Koyanagi-Harada disease

Liu¹,

Jiang²,

Lv³

et al. 2022

JCI Insight

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Vogt-Koyanagi-Harada (VKH) disease is an important refractory uveitis mediated by pathological T cells (TCs). Tofacitinib (TOFA) is a Janus kinases (JAKs) targeted therapy for several autoimmune diseases. However, the specific pathogenesis and targeted therapeutics for VKH remain largely unknown. Based on single-cell RNA sequencing and mass cytometry, we present the first multimodal high-dimensional analysis to determine a comprehensive human immune atlas of VKH patients undergoing TOFA therapy in the context of subset composition, gene signatures, enriched pathways, and intercellular interactions. VKH patients are characterized by TCs polarization from naive to effector and memory subsets, altogether with accrued monocytes, upregulated cytokines and JAK-STAT signaling pathways. In vitro, TOFA reversed Th17/ regulatory T-cell (Treg) imbalance and inhibited IL-2-induced STAT1/3 phosphorylation. TOFA alleviated VKH symptoms by restoring pathological TCs polarization and functional marker expression and downregulating cytokine signaling and lymphocyte function. Remarkably, inflammation-related responses and intercellular interactions decreased after TOFA treatment, particularly in monocytes. Notably, we identified two inflammation-and JAK-associated monocyte subpopulations that were strongly implicated in VKH pathogenesis and mechanisms involved in TOFA treatment. Here, we provide a novel JAK-targeted therapy for VKH and elaborate on the possible therapeutic mechanisms of TOFA, expanding our knowledge of VKH pathological patterns.

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Tofacitinib Suppresses Several JAK-STAT Pathways in Rheumatoid Arthritis In Vivo and Baseline Signaling Profile Associates With Treatment Response

Cited by 33 publications

References 41 publications

Novel Small Molecule Tyrosine Kinase 2 Pseudokinase Ligands Block Cytokine-Induced TYK2-Mediated Signaling Pathways

Novel Small Molecule Tyrosine Kinase 2 Pseudokinase Ligands Block Cytokine-Induced TYK2-Mediated Signaling Pathways

Tofacitinib May Inhibit Myofibroblast Differentiation from Rheumatoid-Fibroblast-like Synoviocytes Induced by TGF-β and IL-6

Insights gained from single-cell analysis of immune cells in tofacitinib treatment of Vogt-Koyanagi-Harada disease

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