Role of JAK-STAT signaling in the pathogenic behavior of fibroblast-like synoviocytes in rheumatoid arthritis: Effect of the novel JAK inhibitor peficitinib.
Rheumatoid arthritis (RA) fibroblast-like synoviocytes (RA-FLS) play a crucial role in the pathogenesis of RA. RA-FLS display passive pro-inflammatory responses and self-directed aggressive responses, such as pro-inflammatory mediator production, reduced apoptosis and formation of a thickened synovial lining. Evidence suggests a role for Janus kinase (JAK)-signal transducer and transcriptional activator (STAT) signaling in the passive response but the aggressive behavior of RA-FLS is poorly understood. The pharmacologic effects of the novel JAK inhibitor, peficitinib, on cytokine-induced intracellular signaling and self-directed aggressive behavior of RA-FLS (e.g., increased expression of apoptosis-resistant genes and sodium nitroprusside-induced apoptosis) were investigated and compared with approved JAK inhibitors. RA-FLS assembly to form a lining-like structure and pro-inflammatory mediator production was investigated in three-dimensional (3D)-micromass culture. Peficitinib inhibited STAT3 phosphorylation in RA-FLS following induction by interferon (IFN)-α2b, IFN-γ, interleukin (IL)-6, oncostatin M, and leukemia inhibitory factor in a concentration-related manner, and was comparable to approved JAK inhibitors, tofacitinib and baricitinib. Peficitinib and tofacitinib suppressed autocrine phosphorylation of STAT3 and expression of apoptosis-resistant genes, and promoted cell death. In 3D-micromass culture, peficitinib reduced multi-layered RA-FLS cells to a thin monolayer, an effect less pronounced with tofacitinib. Both compounds attenuated production of vascular endothelial growth factor-A, matrix metalloproteinases, IL-6 and tumor necrosis factor superfamily-11. This study confirmed the pathogenic role of uncontrolled JAK-STAT signaling in the aggressive and passive responses of RA-FLS that are critical for RA progression. The novel JAK inhibitor peficitinib suppressed the pro-inflammatory behavior of RA-FLS, accelerated cell death and abrogated thickening of the synovium.
Emori T
，Kasahara M
，Sugahara S
，Hashimoto M
，Ito H
，Narumiya S
，Higashi Y
，Fujii Y
... -
《-》
Nonclinical evaluations of deucravacitinib and Janus kinase inhibitors in homeostatic and inflammatory pathways.
Translational medicine provides insight into novel drugs and predicts unwanted effects. In well-characterized pathways (e.g., cytokine-Janus kinase [JAK]-signal transducers and activators of transcription [STAT]), a variety of in vitro assessments were used to estimate selectivity of effects on different potential targets (i.e., JAK1, JAK2, JAK3, and tyrosine kinase 2 [TYK2]). Several approved drugs were characterized as selective for the JAK family. These assessments are challenged by a lack of compounds that only inhibit one JAK family member. Deucravacitinib is a first-in-class, oral, selective, allosteric inhibitor of TYK2, a kinase required for IL-12, IL-23, and Type I interferon signaling. Unlike deucravacitinib, which selectively binds to the TYK2 regulatory domain, JAK1,2,3 inhibitors target the catalytic domain, contributing to nonselective targeting of JAK1,2,3. Cytokines associated with JAK1,2,3 signaling are required for both immune and nonimmune functions. A similar laboratory abnormality profile was observed in clinical trials using JAK1,2,3 inhibitors that has not been observed with deucravacitinib. In vitro testing of JAK1,2,3 inhibitors has relied upon assays of signal transduction, such as those measuring STAT phosphorylation, for estimates of potency and selectivity. These assay systems can be effective in estimating in vivo efficacy; however, they may not provide insight into downstream outcomes of receptor signaling, which may be more relevant for evaluating safety aspects. Assay systems assessing functional outcomes from cells may yield a more useful translational evaluation. Here, deucravacitinib was assessed for potency and selectivity versus three representatives of the JAK inhibitor class (tofacitinib, baricitinib, and upadacitinib) based on functional assays. JAK inhibitors had suppressive activity against JAK2-dependent hematopoietic colony-forming assays modeling thrombopoiesis, erythropoiesis, and myelopoiesis; however, deucravacitinib did not. Deucravacitinib had limited potency against NK cells, cytotoxic T cells, T-helper cells, and regulatory T cells activated by JAK1/JAK3-dependent common gamma chain cytokines. These data are consistent with the biologic role of JAK1,2,3 and pharmacodynamic changes in clinical laboratory abnormalities. Against TYK2-dependent cytokines, deucravacitinib selectively inhibited Type I interferon stimulation of monocytes and dendritic cells and was a more potent inhibitor than JAK inhibitors. IL-12 and IL-23 functional outputs were similarly potently inhibited by deucravacitinib. Results are consistent with deucravacitinib selectively inhibiting TYK2.
Johnson B
，Cheng L
，Koenitzer J
，Catlett IM
，Schafer P
... -
《Frontiers in Immunology》
Baricitinib Ameliorates Experimental Autoimmune Encephalomyelitis by Modulating the Janus Kinase/Signal Transducer and Activator of Transcription Signaling Pathway.
Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) and a CD4+ T cell-mediated autoimmune disease. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is recognized as the major mechanism that regulates the differentiation and function of T helper (Th) 1 and Th17 cells, which are recognized as pivotal effector cells responsible for the development of EAE. We used baricitinib, a JAK 1/2 inhibitor, to investigate the therapeutic efficacy of inhibiting the JAK/STAT pathway in EAE mice. Our results showed that baricitinib significantly delayed the onset time, decreased the severity of clinical symptoms, shortened the duration of EAE, and alleviated demyelination and immune cell infiltration in the spinal cord. In addition, baricitinib treatment downregulated the proportion of interferon-γ+CD4+ Th1 and interleukin-17+CD4+ Th17 cells, decreased the levels of retinoic acid-related orphan receptor γ t and T-bet mRNA, inhibited lymphocyte proliferation, and decreased the expression of proinflammatory cytokines and chemokines in the spleen of mice with EAE. Furthermore, our results showed the role of baricitinib in suppressing the phosphorylation of STATs 1, 3, and 4 in the spleen of EAE mice. Therefore, our study demonstrates that baricitinib could potentially alleviate inflammation in mice with EAE and may be a promising candidate for treating MS.
Dang C
，Lu Y
，Chen X
，Li Q
... -
《Frontiers in Immunology》
ResearchGate
(全网免费下载)
钛学术
(全网免费下载)
