Explore chapters and articles related to this topic
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The Janus Kinases (JAKs) are a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway (Figure 6.65). The abbreviation “JAK” originally stood for “Just Another Kinase” as JAK1 and JAK2 were just two of many kinases identified in a PCR-based kinase screen. However, they were eventually referred to in a publication as “Janus kinases” named after Janus, the two-faced Roman god of duality, due to the presence of two near-identical phosphate-transferring domains, one of which exhibits the kinase activity while the other provides negative regulation.
Newer Agents in Systemic Treatment
Published in Vineet Relhan, Vijay Kumar Garg, Sneha Ghunawat, Khushbu Mahajan, Comprehensive Textbook on Vitiligo, 2020
Rachita Dhurat, Shilpi Agarwal
Currently, four important members of the JAK family are known. Janus kinase 1 and Janus kinase 2 are involved in host defense, hematopoiesis, neural development, and growth. Janus kinase 3 and tyrosine kinase 2 have a role in the immune response [32].
Overview of JAK-STAT Pathways in Spondyloarthritis
Published in Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi, Psoriasis and Psoriatic Arthritis, 2017
Smriti K. Raychaudhuri, Sanchita Raychaudhuri, Debasis Bagchi, Anand Swaroop, Siba P. Raychaudhuri
The Janus kinases (JAKs) belong to a family of intracellular tyrosine kinases and are associated with the signaling process of several cytokines [11,12]. JAKs play a critical role in (1) hematopoiesis, (2) adaptive immunity, and (3) innate immunity [11–14]. Several JAK inhibitors have been developed; these are oral synthetic compounds. In this chapter, we describe the functional significance of the JAK-STAT (signal transducers and activators of transcription) signaling proteins in the inflammatory-proliferative cascades of SpA and potential applications of the JAK-STAT kinase inhibitors in psoriatic disease and ankylosing spondylitis (AS).
Therapeutic potential of JAK inhibitors in juvenile idiopathic arthritis-associated uveitis
Published in Expert Review of Clinical Immunology, 2023
Ilaria Maccora, Preston Land, Virginia Miraldi Utz, Sheila T Angeles-Han
In uveitis, dysregulated activation of the immune system leads to hyper-activation of T Cells (Th1 and Th17) and B cell subsets [7]. Studies in models of experimental autoimmune uveitis and in biospecimens such as aqueous humor and tears highlight the crucial role of Th1 and Th17 as in the development of uveitis, triggering the inflammatory cascade [7,9]. The secretion of inflammatory mediators such as cytokines (IL-6, TNF-α, interferon-gamma [IFN-γ], IL-2, and IL-17), and chemokines amplify the inflammatory cascade. Recruitment of additional inflammatory cells and increased cytokines and chemokines locally leads to a consequent breakdown of the blood retina barrier [7,8]. Cytokines and chemokines interact with their receptors resulting in receptor oligomerization with subsequent activation and phosphorylation of JAK. Subsequently, JAK phosphorylates the signal transducer and activator of transcription (STATs), a superfamily of DNA binding proteins (STAT1, 2, 3, 4, 5A, 5B, and 6) [7,8]. After phosphorylation, STAT will then dimerize and translocate to the nucleus, where it regulates the expression of specific genes critical for enhancing inflammation [7]. Different ligand and receptors activate different subtypes of JAK, which then influence inflammatory cell proliferation, development, differentiation, migration, and apoptosis [7]. In this context, Janus Kinase acts as a signaling pathway mediator for cytokines and chemokines by transducing the signals affecting and regulating the immune response6.
Ritlecitinib: an investigational drug for the treatment of moderate to severe alopecia areata
Published in Expert Opinion on Investigational Drugs, 2021
Samantha Eisman, Rodney Sinclair
The Janus kinase (JAK) family includes JAK1, JAK2, JAK3, and TYK2. They are a group of cytoplasmic tyrosine kinases that mediate signal transduction via interactions with types 1 and 2 cytokine receptors [14,15]. These receptors are critical for leukocyte activation, proliferation, function and survival. JAKs are activated, and phosphorylate each other and their receptor, when the cytokines bind to this receptor. Once the receptors are phosphorylated, they serve as a docking station for the signal transducer and activator of transcription (STAT) family of transcription factors. The STATs are phosphorylated and then subsequently translocated to the nucleus where they bind to specific gene promoters to activate transcription of a range of target genes. JAK inhibitors therefore affect activation, proliferation, and function of leukocytes [14].
Regulation of T cell differentiation by the AP-1 transcription factor JunB
Published in Immunological Medicine, 2021
Takaharu Katagiri, Hideto Kameda, Hiroyasu Nakano, Soh Yamazaki
As mentioned above, therapeutic methods targeting transcription factors have not yet been established. However, recent advances in multi-targeted treatments have been remarkable owing to kinase-targeted treatments such as Janus kinase inhibitors. Targeting the expression or function of JunB may allow regulation of the differentiation of Th17 cells, which is likely to be a distinct therapy from biological agents against IL-17 or its receptors. However, such therapy may reduce Treg cells and, therefore, concomitant administration of an appropriate dose of IL-2 may improve the risk-benefit balance of JunB-targeting therapy. Conversely, evaluation of JunB expression level in patients with autoimmune diseases may allow physicians to determine the appropriate dose of IL-2 to avoid excessive effector T cell activation. Thus, a balance between Th17 and Treg cells via regulation of JunB is imperative to achieve better therapeutic outcomes in autoimmune diseases.