Immune-mediated chronic inflammatory diseases have emerged as a leading cause of morbidity and mortality in Western countries over the last decades. Although multiple putative factors have been suspected to be causally related to the diseases, their overarching etiology remains unknown. This review article summarizes the current state of scientific knowledge and understanding of the role of non-receptor tyrosine kinases, with a special focus on the Janus kinase TYK2 in autoimmune and immune mediated diseases as well as on the clinical properties of its inhibition. A panel of experts in the field discussed the scientific evidence and molecular rationale for TYK2 inhibition and its clinical application. Reviewing this meeting, we aim at providing an integrated overview of the clinical profile of TYK2 inhibition and its potential in targeted pharmacological therapy of chronic autoimmune and immune-mediated diseases, with a special focus on inflammatory diseases of the skin.
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http://dx.doi.org/10.1111/ddg.14585 | DOI Listing |
Adv Biol Regul
December 2024
Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpönkatu 34, 33014, Finland; Institute of Biotechnology, HiLIFE, University of Helsinki, P.O. Box 56, 00014, Finland; Department of Microbiology, Fimlab Laboratories, P.O.Box 66, 33013, Tampere, Finland. Electronic address:
Janus kinases (JAK1-3, TYK2) are critical mediators of cytokine signaling and their role in hematological and inflammatory and autoimmune diseases has sparked widespread interest in their therapeutic targeting. JAKs have unique tandem kinase structure consisting of an active tyrosine kinase domain adjacent to a pseudokinase domain that is a hotspot for pathogenic mutations. The development of JAK inhibitors has focused on the active kinase domain and the developed drugs have demonstrated good clinical efficacy but due to off-target inhibition cause also side-effects and carry a black box warning limiting their use.
View Article and Find Full Text PDFMediators Inflamm
January 2025
Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan.
RMD Open
December 2024
The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Fukuoka, Japan
In systemic lupus erythematosus (SLE), adaptive immunity is activated by the stimulation of innate immunity, leading to the development of autoreactive T cells and activation and differentiation of B cells. Cytokine signalling plays an essential role in the pathogenesis and progression of this disease. In particular, the differentiation and function of CD4+ T cell subsets, which play a central role in SLE pathology, are significantly altered by cytokine stimulation.
View Article and Find Full Text PDFExp Mol Pathol
December 2024
Rheumatology Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari, Bari, Italy.
Interleukin-6 (IL-6) is a relevant cytokine in rheumatoid arthritis (RA) pathogenesis, potentially activating Janus kinases (JAK)-1, -2, and tyrosine kinase 2 (TYK2), and thus, three signal transducer and activator of transcription (STAT)-1, -3 or - 5 pathways. This pilot study aims to explore differences in phosphorylated (p)STAT3 levels among patients with RA, those not classified as RA (nRA), and healthy donors (HD), providing some clues on the relative contribution of each JAK protein to the downstream of the IL-6-induced STAT3 pathway. Clinical data and blood samples from 80 subjects (41 RA, 14 nRA, and 25 HD) were collected.
View Article and Find Full Text PDFCell Biol Toxicol
December 2024
The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China.
Synovial sarcoma (SS) is a rare soft tissue sarcoma characterized by high-grade malignancy and poor prognosis. Preliminary research indicates that apoptosis evasion is a key factor in SS progression, primarily attributed to the overexpression of anti-apoptotic genes. However, the mechanisms underlying this phenomenon are still not fully understood.
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